Introduction to the Role

Introduction to the Role
of Cytokines in Innate
Host Defense and
Adaptive Immunity
Joost J. Oppenheim
1,
*
and Marc Feldmann
2
1
Laboratory of Molecular Immunoregulation, Division of Basic Sciences, National Cancer Institute,
Frederick, MD 21702-1201, USA
2
Cytokine and Cellular Immunology Division, Kennedy Institute of Rheumatology,
1 Aspenlea Road, Hammersmith, London, W6 8LH, UK
*corresponding author tel: 301-846-1551, fax: 301-846-7042, e-mail: [email protected]
DOI: 10.1006/rwcy.2000.01001.
HISTORICAL OVERVIEW
Although the methods available prior to 1970
permitted only phenomenological detection of biolo-
gical activities, the possibility that host factors were
responsible for fever was suggested over 50 years ago.
The first to propose that soluble factors modulated
host reactions was Menkin, who `purified' fever-
inducing activities from inflammatory exudates and
called them `pyrexin' (Menkin, 1944). These factors
were subsequently shown to survive boiling and to be
contaminated by bacterial pyrogens (endotoxin).
Bennett and Beeson in 1953 were able to separate
an endogenous pyrogen (EP) from endotoxin present
in acute inflammatory exudates and were also able to
extract EP from peripheral blood leukocytes.
Analogous intercellular signals, namely nerve growth
factors, were discovered by Levi-Montalcini and
Hamburger (1953). They observed that implanted
mouse sarcoma cells produced an agent that induced
marked growth and differentiation of distant sympa-
thetic ganglia of chick embryos. Interferons were
discovered by Isaacs and Lindenmann (1957), as
nonantibody cell-derived factors that induced host
cells to become inhospitable to viruses and inhibit
viral replication.
The era of `lymphodrek'
Immunologists, however, should be credited for the
enthusiastic pursuit of studies of mediators of host
defense. The concept that `humoral factors' might be
responsible for cell-mediated host defenses could be
readily understood by immunologists who were
accustomed to the concept of specific antibody-
mediated reactions. The identification of lymphocytes
as the principal immunocompetent cells by Gowans
(1959) and the development of tissue culture tech-
niques for studies of in vitro lymphoproliferative
reactions to a polyclonal stimulant, namely phytohe-
magglutinin, by Nowell (1960), laid the groundwork
for the detection of lymphocyte-derived soluble
mediators by immunologists. These critical observa-
tions were reinforced by the demonstrations by
Pearmain et al. (1963) that only lymphocytes from
tuberculin-sensitive donors could undergo blastogen-
esis in response to tubercle antigens. The idea that
antigens induced specific in vitro proliferative repeti-
tions was reinforced by the observations of Bain et al.
(1964) who showed that allogeneic mixed leukocyte
cultures also resulted in lymphocyte blastogenesis.
Three successive discoveries between 1964 and 1967
by independent laboratories initiated the studies of
the effects of `factors in culture supernatants' by
immunologists. Kasakura and Lowenstein (1965) were
the first to detect the presence in supernatants of
antigen- or alloantigen-stimulated leukocyte cultures
of mitogenic or blastogenic factors (BFs) that were
not attributable to antibodies. This was rapidly
followed by the detection in such supernatants of
immunologically nonspecific macrophage migration
inhibitory factors (MIFs) by David (1966) and Bloom
and Bennett (1966) and of a cytotoxic factor called
lymphotoxin (LT) by Ruddle and Waksman (1967)
and Granger and Williams (1968). These three
activities were considered to be in vitro `correlates'
or indicators of cellular immunity that could be
induced by specific in vitro immune responses.
Immunologists became fascinated with these non-
specific lymphoproliferative factors and effectors of
host defense and were very intrigued by mitogenic
growth factors as mediators of lymphocyte replica-
tion. Kasakura and Lowenstein (1965) reported that
leukocytes stimulated by bidirectional allogeneic
mixed leukocyte reactions (MLRs) secreted BFs.
The supernatants of MLRs were considerably more
mitogenic than those from unstimulated leukocytes,
while cell extracts were completely inactive. Gordon
and MacLean (1965) demonstrated that inhibition of
the blastogenic response in an MLR by puromycin or
5-fluorouracil also blocked the production of BFs,
suggesting that BF was newly synthesized by lym-
phoblasts. Since unstimulated leukocytes from auto-
logous as well as homologous donors were induced by
BFs to synthesize DNA and RNA to enter the cell
cycle, Kasakura and Lowenstein (1967) demonstrated
for the first time that specific alloantigen-stimulated
leukocyte cultures could generate immunologically
nonspecific mitogenic factors. Dumonde et al. (1969)
reported that these nonantibody secretory mitogenic
factors were products of antigen-activated lym-
phocytes and coined the term `lymphokines' for
lymphocyte-derived mediators.
Although many laboratories in the 1970s attempted
to characterize MIFs, in retrospect this indirect assay
of induction of macrophage adhesion proteins led up
a blind alley and did not result in any progress in our
understanding of the processes of host defense. In
fact, a number of cytokines such as interferon have
been shown to have MIF activity and the physiolo-
gical role of the recently cloned cytokine with `MIF
activity' remains unclear (Weiser et al., 1989 and as
reviewed by Bernhagen et al., 1993). Studies of factors
acting on macrophages led to the more readily inter-
pretable observation that antigen-stimulated lympho-
cyte cultures also produce a macrophage-activating
factor (MAF), which nonspecifically arms macro-
phages to kill intracellular bacteria (Nathan et al.,
1971). Immune interferon (IFN) was subsequently
reported to have potent MAF activity (as reviewed by
Schreiber and Celada, 1985). MAF was considered a
major lymphocyte-derived nonspecific mediator of
host defense. Studies of lymphotoxin were amplified
by the subsequent discovery by Carswell et al. (1975)
of serum factors with in vitro cytotoxic effects that
induced in vivo tumor necrosis (tumor necrosis factor,
TNF). TNF production was induced by endotoxin
and, in contrast to lymphocyte-derived LT, was
predominantly a macrophage-derived product. Both
of these factors were considered to contribute to host
defense against infectious and neoplastic diseases.
The advent of nonlymphocytic
cytokines
In an independent but convergent line of research,
Gery and colleagues (Gery et al., 1971; Gery and
Waksman, 1972) reported that activated macrophages
secreted a mitogenic factor for thymocytes called
lymphocyte-activating factor (LAF). This represented
the first report that nonlymphocytes could also
produce growth factors acting on lymphocytes. Based
on the overlap in the biochemical and biological acti-
vities of LAF and endogenous pyrogens (EPs had
mitogenic effects on thymocytes, while LAF was
pyrogenic), Rosenwasser et al. (1979) were the first to
propose that these activities might be attributable to
the same molecule. This observation permitted rapid
progress in the subsequence purification and identi-
fication of endogenous pyrogen by substituting a
simple quantitative LAF assay for in vivo fever
assays.
Cohen was the first to observe that MIF-like acti-
vities could be produced by a variety of nonmacro-
phage and nonlymphocytic cell lines (e.g. fibroblasts).
This observation and the recognition by Gery that
macrophages produced `monokines' such as LAF led
Cohen to propose the more inclusive term of `cyto-
kines' for the family of polypeptides secreted by a
variety of cell types that engage in immunologically
mediated inflammatory reactions (Cohen et al., 1974).
Cytokines at present are defined as soluble, extra-
cellular proteins that regulate innate as well as immu-
nologically regulated inflammatory reactions, cell
growth, differentiation, development, and repair
4 Joost J. Oppenheim and Marc Feldmann
processes culminating in the restoration of
homeostasis.
By 1978 a review by Waksman listed almost 100
apparently distinct cytokine activities, many more
than can be listed in our chronological review
(Table 1). At the second International Lymphokine
Workshop held in Ermatingen, Switzerland in 1979,
advances in techniques for characterizing the biolo-
gical and biochemical properties of a number of these
cytokine activities fostered the mistaken belief that
most of these activities could be attributed to only a
few molecules and culminated in their renaming as
either interleukin 1 or interleukin 2 (see review by
Oppenheim and Gery, 1993). This idea led to the
substitution of a more `generic' interleukin terminol-
ogy for the numerous confusing acronyms based on
the activities of these cytokines. It was proposed that
monocyte/macrophage-derived mitogenic factors
such as LAF/EP, T cell-replacing factor III, B
cell-activating factor and differentiation factor be
renamed interleukin 1 (IL-1). The lymphocyte-derived
mitogenic factors such as lymphocyte mitogenic
factor (LMF)/BF, killer helper factor (KHF) and T
cell growth factor (TCGF) were renamed IL-2 (Mizel
and Farrar, 1970). The discoverers of TCGF
(Morgan et al., 1976) resisted this change in ter-
minology on the grounds that their descriptive term
accurately reflected the activity of this lymphokine.
However, the controversy was resolved by reports
that IL-2 is also a proliferative signal for B cells
(Zubler et al., 1984) and natural killer (NK) cells
(Ortaldo et al., 1984). Despite the fact that many of
the cytokines, such as IL-1, can be produced by and
also act on nonleukocytic somatic cells as well as
leukocytes (Oppenheim and Gery, 1982), the inter-
leukin nomenclature has been accepted; we are now
up to IL-18. A number of the other cytokines,
including TNF, LT (now also known as TNF), the
Table 1 Chronology of cytokine discoveries
Date Discoverers Mediators
1944 Menkin Fever-inducing `pyrexin' in exudates
1953 Bennett and Beeson Endogenous pyrogen in exudates
1953 Levi-Montalcini and Hamburger Nerve growth factor
1957 Isaacs and Lindenmann Nonantibody interferons (IFN)
1965 Kasakura and Lowenstein Blastogenic factors for lymphocytes
1966 David, and Bloom and Bennett Macrophage migration inhibitory factor
1967 Ruddle and Waksman Lymphotoxin
1969 Dumonde et al. Named lymphocyte-derived factors `lymphokines'
1969 Ward et al. Chemoattractants for monocytes and neutrophils
1971 Nathan et al. Macrophage-activating factor
1971 Gery et al. Macrophages ± source of
`lymphocyte-activating factor' (LAF)
1974 Cohen et al. Nonleukocytes also produce `cytokines'
1975 Carswell et al. Tumor necrosis factors
1976 Morgan et al. T cell growth factor
1979 2nd International Lymphokine
Workshop (reviewed by Mizel and Farrar, 1970)
Nonlymphocyte- and lymphocyte-derived
mitogenic factors renamed interleukin 1
and 2 (IL-1 and IL-2) respectively
1980 Taniguchi et al., Nagata et al. Cloning of IFN1 and IFN1 respectively
1981 Ihle et al. IL-3 growth factor for hematopoietic progenitors
1982 Gray et al. Cloning of IFN
1984 Leonard et al. Cloning of IL-2 receptor chain
1985 Derynck et al. Cloning of transforming growth factor (TGF)
1986 Mosmann et al. Identification of CSIF/IL-10
1986 Zilberstein et al. Sequenced IFN2 and renamed it IL-6
Introduction to the Role of Cytokines in Innate Host Defense and Adaptive Immunity 5
IFNs and colony-stimulating factors (CSF) escaped
being renamed. The initial intent to restrict the inter-
leukin terminology to lymphocyte-targeted cytokines
was very short-lived, however, with the naming of a
lymphokine that acts predominantly as a multi-CSF
and is a growth factor for hematopoietic progenitor
cells rather than lymphocytes as IL-3 (Ihle et al., 1981).
The molecular period
The molecular cytokine era began soon after the
Ermatingen meeting with the development of newer
technologies such as high-performance liquid chro-
matography (HPLC), microsequencing, and the pro-
duction of monoclonal antibodies to cytokines. These
developments permitted the purification and amino
acid sequencing of the minuscule quantities of cyto-
kines secreted into culture supernatants. Application
of molecular biological techniques revolutionized the
cytokine field further by making available larger
quantities of cloned and expressed recombinant cyto-
kines and also resulted in the identification of more
cytokines by direct expression gene cloning. These
new technologies have led to the discovery of numer-
ous new cytokines and have modified our concepts
concerning the spectrum of activities ascribed to
previously described cytokines. The first cytokine to
be cloned in 1980 by Taniguchi and his colleagues ±
IFN1 ± was rapidly followed by the cloning of
IFN1 by Nagata et al. (1980). To date, about 16±20
variants of IFN have been identified, all of which
interact with the same cell surface receptor and pro-
mote antiviral resistance. This was followed by the
cloning of IFN, by Gray and his colleagues at
Genentech (Gray et al., 1982). The following year saw
the cloning of IL-2 by Taniguchi with collaborators at
Ajinimoto Corp. (Taniguchi et al., 1983). Availability
of the recombinant form of IL-2 enabled many
investigators to confirm this lymphokine to be a major
lymphoproliferative cytokine for T cells, B cells, and
NK cells. IL-2 also enhances the activities of lym-
phoid cells either directly or indirectly by inducing the
production of a variety of other immunostimulating
cytokines such as IFN, TNF, and IL-1. Additional
lymphoproliferative growth factors in BF/LMF pre-
parations such as IL-4, IL-6, IL-7, IL-9, IL-10, IL-13,
and IL-15 have since been identified.
The cytokine receptor phase
In 1984, the first of the three chains in the IL-2
receptor, IL-2R, was cloned by Leonard and colle-
agues, thus ushering in the present era of the `cytokine
receptor'. During 1984 the two cytotoxic factors LT
(renamed TNF) and TNF (designated TNF) were
also cloned and expressed by Pennica et al. (1984) and
Gray et al. (1984), respectively. The development of
new technologies permitting the generation of mice
with targeted deletion of TNF or LT genes has
drastically altered our perception of reality (Durum
and Muegge, 1998). Rather than being defined as a
cytotoxic factor, this revealed that mice lacking LT
fail to develop peripheral lymph nodes, and have
disorganized splenic tissue deficient in germinal
centers and as a result are immunodeficient. These
studies showed for the first time that LT plays a
pivotal role in the development of peripheral lym-
phoid tissues. In contrast, TNF depletion generated
mice with only limited disorganization of the peri-
pheral lymphoid tissues, but they exhibited reduced
resistance to infectious challenges. These studies
revealed TNF to be a key regulator of inflammation
in host defense rather than a cytotoxic antitumor
factor. The antitumor effects of TNF are not based
on tumor cytotoxic effects, but are actually largely
due to the capacity of TNF to stimulate endothelial
cells of newly formed blood vessels to produce
clotting factors which results in their occlusion and
thus the central necrosis of tumors. The differences
between TNF and LT also led to the prediction that
they must use receptors in addition to TNFRI and
TNFRII. Consequently, receptors specific for LT
have been identified as LTR, because it binds a
heterotrimer of LT/LT2. Another member of the
TNF family, Fas, has actually been identified as a
potent cytotoxic factor (Nagata and Golstein, 1995;
Nagata, 1997). Mice with defective gld gene products
that lack a functional Fas ligand as well as mice who
have homolozygous defective lpr genes for the Fas
receptor are unable to eliminate lymphocytes and
develop marked lymphoid hyperplasia and severe
autoimmune syndromes. The TNF family continues
to expand at an alarming rate and novel members of
the TNF family are still being identified to date.
The identification of suppressive
cytokines
A number of cytokines have been identified that act
predominantly as downregulators of inflammatory
and immune responses. The first of the cytokines
which proved subsequently to have potent nonspecific
immunosuppressive and anti-inflammatory effects,
namely transforming growth factor (TGF) was
cloned in 1985 by Derynck with his colleagues at
Genentech and with collaborators at the NIH
(Derynck et al., 1985). In addition, a `cytokine
6 Joost J. Oppenheim and Marc Feldmann
synthesis inhibitory factor' (CSIF) initially discovered
by Mosmann and colleagues (Moore et al., 1990)
functions as a pivotal immunomodulator. CSIF, now
renamed IL-10, has immunoenhancing effects on
humoral immunity as well as considerable immuno-
suppressive effects on cell-mediated immune res-
ponses. It should be noted that some viruses subvert
the immune response by producing homologs of
mammalian cytokines or their receptors. This is
exemplified by the Epstein±Barr virus (EBV) which
produces a homolog `virokine' version of IL-10 which
has only the immunosuppressive and B cell-stimulat-
ing, but lacks the T cell-stimulating capacities of the
mammalian cytokine. EBV has therefore cleverly
mutated the cytokine to suppress host resistance and
promote the growth of its target B cells. It is the first
of many virally encoded cytokine ligand and receptor
homologs that act as agonists or antagonists to
subvert host defenses.
Chemotactic cytokines
(`chemokines')
The interest in chemotactic cytokines began with the
report of Ward and colleagues showing that antigen
induced lymphocytes to produce chemoattractants
for monocytes (Ward et al., 1969). Investigators in the
1970s identified mononuclear cells as a source of
neutrophil chemoattractants and these were subse-
quently attributed to partially purified preparations
of natural IL-1 (Luger et al., 1983; Sauder et al.,
1984). Leonard and Oppenheim subsequently realized
that more purified preparations of recombinant IL-1
failed to act as chemoattractants. This led Yoshimura
et al. (1987) to purify these `contaminant' chemoat-
tractant cytokines in their laboratories and these
efforts culminated in the cloning of a monocyte-
derived neutrophil chemotactic factor (MDNCF),
also known as neutrophil-attracting protein 1
(NAP-1), by Matsushima et al. (1988). MDNCF
also was observed to chemoattract T cells as well as
neutrophils and was therefore renamed IL-8 (Larsen
et al., 1989). To date a large superfamily of cytokines
with more than 50 distinct members of structurally
related chemoattractants acting on every inflamma-
tory cell type has been cloned. These `chemoattrac-
tant cytokines' are now called chemokines for short.
Chemokines have been shown to regulate the adhe-
sion of leukocytes to endothelial cells, to promote
diapedesis and migration of leukocytes into inflam-
matory sites, to costimulate immune responses,
enhance allergic reactions, to regulate angiogenesis,
influence hematopoiesis and to promote the homing
of T cells and B cells to their proper locations in
lymphoid tissues.
The IL-6 family
The amino acid sequence of IL-6 was actually first
reported as a so-called 26 kDa protein by Content
et al. in 1982. This product of fibroblasts was thought
to have antiviral activity and was therefore mis-
identified as IFN-B2. A protein termed B cell dif-
ferentiation factor (BCDF) or B cell-stimulating
factor 2 (BSF-2) based on its capacity to induce
antibody secretion by B cells was cloned by Hirano
et al. in 1986. BCDF/BSF-2 was renamed IL-6 and
found to be identical to IFN-B2 (Zilberstein et al.,
1986; Poupart et al., 1987). Although IL-6 does not
have any antiviral activity, it may induce cells to
produce IFN. IL-6 also was identified as an
`hepatocyte-stimulating factor' based on its capacity
to induce acute phase protein production by cultured
hepatocytes (Andus et al., 1988). IL-6 also plays an
important role in early hematopoietic cell prolifera-
tion and differentiation. A number of ligands that are
closely related to IL-6 in using a common receptor
chain were subsequently discovered as will be
discussed. It is beyond the scope of this chapter to
discuss the discovery of all the remaining interleukins
in detail, but we will discuss the discovery of some of
the receptors with which the interleukins interact.
Cytokines today
Today, we are again confronted by considerably
more than 100 cytokines, but this time they are
structurally identified molecules that exhibit unique
as well as many redundant activities (as reviewed by
Oppenheim and Saklatvala, 1993). The observations
that some of these cytokines, although themselves
structurally distinct, share receptors or receptor
chains may account for some of this redundancy.
The identification of cytokine receptor families has
established relationships between groups of structu-
rally independent cytokines that by sharing receptors
presumably go on to use the same signal transduction
pathways. This is amply illustrated by the 20 IFN
variants as well as IFN and IFN! which all share
the same receptor, nuclear-binding proteins, and
antiviral activities. They are distinguished from IFN
which binds to a different receptor and possesses both
antibacterial and antiviral activities. However, recep-
tors can have disparate functions. Two receptors for
IL-1 have been identified which belong to the
immunoglobulin superfamily. Both IL-1 and IL-1
Introduction to the Role of Cytokines in Innate Host Defense and Adaptive Immunity 7
bind to each of these receptors with equal affinity.
The type I receptor, however, is solely responsible for
signal transduction while the nonsignaling type II
receptor sequestrates both IL-1 and IL-1 on the
cell surface, or when shed in soluble form is able to
selectively bind IL-1 and can serve as an inhibitor of
IL-1 activities. TNF and LT, although only 28%
homologous in amino acid sequence, share the same
two TNF receptors, each of which activates some
distinct cellular activities. Binding of TNF or LT to
the smaller p55 receptor results in cytotoxic events,
while binding to the p75 TNF receptor favors lym-
phoproliferative responses. These two TNF receptors
exhibit unexpected homology to receptors for distinct
cytokines with unrelated activities such as nerve
growth factor (NGF), to cytokine receptors resulting
in apoptotic consequences such as Fas, or with costi-
mulatory lymphoproliferative effects as for CD27,
CD30, and CD40. Observations relating these cyto-
kines to one another based on receptor homology and
sharing has accelerated the characterization of newly
identified members of the TNF family.
Most of the receptors for the colony-stimulating
factors (e.g. IL-3, GM-CSF, and G-CSF) as well as
for many of the lymphoproliferative interleukins are
members of the hematopoietin receptor family. A
number of these cytokines share a receptor chain. The
receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 all
appear to share a chain, which presumably con-
tributes to the signal transduction by these lympho-
proliferative cytokines. This may also account for the
recent observation that defects in the IL-2 receptor
chain result in a much more severe human immu-
nodeficiency state (Schorle et al., 1991) than is
obtained by a defect in IL-2 as in IL-2 knockout mice
(DiSanto et al., 1995). Similar results reviewed by
Miyajima et al. (1992) indicate that three of the
hematopoietic growth factors (GM-CSF, IL-3, and
G-CSF) share a signal transducing chain. Finally,
the discovery that the IL-6 receptor pl30 signal
transducer is shared by leukemia inhibitory factor
(LIF), oncostatin M, IL-11, ciliary neurotropic factor
(CNTF) and cardiotropin 1 (CT-1) has accelerated
characterization of IL-6 family members (as reviewed
by Taga and Kishimoto, 1997).
WHAT ARE CYTOKINES?
The original view of `cytokines' described above rested
on the concept that these were extracellular protein
messenger molecules produced by cells involved in
inflammation, immunity, differentiation, cell division,
fibrosis repair, etc. However, molecular character-
ization of these proteins has revealed that many
(e.g. TNF, IL-1, TGF) are also functional as cell
surface signaling molecules (Kriegler et al., 1988).
Gene cloning has revealed that cytokines with
varying degrees of amino acid homology belong to a
number of cytokine families (Smith et al., 1994;
Dinarello, 1998). Some members of these families are
predominantly, if not exclusively, active as the cell
surface form (e.g. CD40 ligands), while others act
exclusively extracellularly. As these molecules share
the same signaling pathways as secreted forms, these
are now also considered cytokines.
All cytokines are proteins, but their physical
characteristics vary. The largest family, the chemo-
kines, are low molecular weight 8±10 kDa polypep-
tides. Some are single-chain proteins (e.g. IL-1),
others, such as IFN, form homodimers, while mem-
bers of the TNF family are trimers, usually homo-
trimers except for lymphotoxin which can be a
heterotrimer. Many of the cytokines are glycosylated.
A distinctive feature of cytokines is that they are
usually not constitutively produced, but are generated
in response to stimulation. Typically their production
cycle lasts a few hours to a few days in the normal
state, but if the stimulus persists, as in a disease state,
then it is possible for cytokine production to be
prolonged (Feldmann et al., 1996a,b).
Virtually all cells can produce cytokines, in response
to diverse stimuli. Which cytokines a cell makes from
its potential repertoire depends on the stimulus, its
nature, duration, intensity, as well as the presence of
other factors ± other cytokines, hormones, cell contact
interaction, etc.
A key feature of cytokines is their `potency' ±
meaning that they are bioactive at very low con-
centrations, often in range 10
À10
to 10
À13
mol/L,
roughly 1 ng
À1
pg/mL. This potency is linked to the
high affinity of their receptors, usually 10
À9
to 10
À12
mol/L, and also that signaling does not require high
receptor occupancy, often 10% will suffice.
The generic classification `cytokine' is now used to
include interferons, discovered as antiviral proteins,
interleukins, molecules initially described as media-
tors between leukocytes, chemokines (chemotactic
cytokines), hematopoietic factors and other growth
factors. The term `lymphokine', denoting a product of
lymphocytes, is no longer commonly used, as most of
the molecules produced by lymphocytes are also
produced by other cells.
Other general discussions of cytokines can be found
in The Cytokine Handbook, Chapter 1 by Jan Vilcek
(Vilcek, 1998), or Section I ± Introduction to Cytokine
Biology in Clinical Applications of Cytokines
(Oppenheim et al., 1993).
A listing of some cytokines grouped into families is
shown in Table 2.
8 Joost J. Oppenheim and Marc Feldmann
Table 2 Cytokine families: examples grouped by structural similarity of ligands and/or receptors
Family Abbreviation Name
Hematopoietins IL-2 Interleukin 2
IL-3 Interleukin 3
IL-4 Interleukin 4
IL-5 Interleukin 5
IL-6 Interleukin 6
IL-7 Interleukin 7
IL-9 Interleukin 9
IL-11 Interleukin 11
IL-12 Interleukin 12
EPO Erythropoietin
LIF Leukemia inhibitory factor
GM-CSF Granulocyte± macrophage
colony-stimulating factor
G-CSF Granulocyte colony-stimulating factor
OSM Oncostatin M
CNTF Ciliary neurotropic factor
GH Growth hormone
TPO Thrombopoietin
TNF family TNF Tumor necrosis factor
LT Lymphotoxin
LT Lymphotoxin
CD40L CD40 ligand
CD30L CD30 ligand
CD27L CD27 ligand
4-1BBL
FasL Fas ligand
IL-1 family IL-1 Interleukin 1
IL-1 Interleukin 1
IL-1Ra Interleukin 1 receptor
antagonist
bFGF Basic fibroblast growth factor
aFGF Acidic fibroblast growth factor
ECGF Endothelial cell growth factor
(CXC) family IL-8 Interleukin 8
GRO// Melanocyte growth-stimulating factor
NAP-2 Neutrophil-activating protein
ENA 78 Epithelial neutrophil-activating peptide
GCP-2 Granulocyte chemotactic protein
PF4 Platelet factor 4
CTAP-3 Connective tissue-activating peptide 3
MIG Monokine induced by IFN
Introduction to the Role of Cytokines in Innate Host Defense and Adaptive Immunity 9
RELATIONSHIP OF CYTOKINES
TO HORMONES AND GROWTH
FACTORS
Although cytokines share properties in common with
hormones and interact with them, there are also
notable distinctions. There are differences between
inducible cytokines, and hormones which are pro-
duced continuously, and growth factors. Hormones
are typically produced by specialized cells and
released into the bloodstream and so can act at a
distance from their source, in an `endocrine fashion'.
In contrast, cytokines typically act at short range, a
few cell diameters apart, as in a `paracrine' (acting on
neighboring cell) or `autocrine' (acting on self) manner.
While levels of hormones are easily measurable
in the serum or plasma, only a few cytokines are
regularly detected there. These include macrophage
colony-stimulating factor (M-CSF), erythropoietin
(EPO), thrombopoietin (TPO), stem cell factor
(SCF), the latent form of TGF, and a chemokine,
SDF1. A summary of the similarities and differ-
ences between hormones and cytokines is shown in
Figure 1.
The properties of growth factors are intermediate
between hormones and the cytokines; these are the
ones most likely to be found in the blood in the
absence of acute stimulation. Many of the receptors
for growth factors like those for many hormones are
kinases (e.g. PDGF, VEGF, FGF), tyrosine kinases
except for the receptors for the TGF family, which
are serine/threonine kinases.
HOW DO CYTOKINES ACT?
Cytokines are produced by most cells. Each cell has
its program of cytokines it can synthesize. Some cell
types suchas macrophages, Tcells, andmast cells make
a very wide spectrum of cytokines. Whereas most
cytokines are produced and soon released, in some
circumstances cytokines are temporarily stored by the
cell. These can be cell surface-bound cytokines which
may (e.g. TNF) or may not (e.g. TGF) be bio-
logically active. Cytokines may be stored intracyto-
plasmically (e.g. IL-1), and may not have an obvious
form of release, or in granules as in mast cells or
platelets. The export into the supernatant is no longer
an obligatory part of cytokine physiology.
Table 2 (Continued )
Family Abbreviation Name
IP-10 IFN-inducible protein 10
I-TAC
(CC) family MCP-1 Monocyte chemoattractant protein 1
MCP-2 Monocyte chemoattractant protein 2
MCP-3 Monocyte chemoattractant protein 3
MIP-1 Macrophage inflammatory protein 1
MIP-1 Macrophage inflammatory protein 1
RANTES Regulated upon activation normal T cell
expressed and secreted
PDGF family PDGF A Platelet-derived growth factor A
PDGF B Platelet-derived growth factor B
CSF Macrophage colony-stimulating factor
SCF Stem cell factor
TGF family TGF Transforming growth factor
Inhibin 2A, 2B
Activin 1, 2A, 2b, 4
BMP 1,
2A, 2B, 4
Bone morphogenetic protein
10 Joost J. Oppenheim and Marc Feldmann
The usual mechanism of action of cytokines is on
neighboring cells, and there are multiple mechanisms
to restrict the diffusion of cytokines. The most wide-
spread mechanism is the presence of receptors on the
cell surface which bind, signal and then usually inter-
nalize the cytokine and lead to its degradation. There
are also, for those receptors with a single transmem-
brane spanning section (which means all except the
chemokine receptors), soluble receptors consisting of
the extracellular domain (Fernandez-Botran, 1991).
These retain cytokine-binding activity and act to limit
the bioavailability of the cytokine, which when bound
to soluble receptor is not free to bind to cell surface
signaling receptor. There are other lower affinity
cytokine inhibitors in the blood, such as
2
-macro-
globulin which binds IL-1. So far there is only one
described competitive inhibitor of cytokines acting on
receptors, the IL-1 receptor antagonist (IL-1Ra)
(Arend, 1993). This gene is alternatively spliced to
generate a number of isoforms, two of which remain
intracytoplasmic. The function of intracytoplasmic
IL-1Ra is not clear. Extracellular IL-1Ra is present in
normal body fluids at appreciable concentrations,
300 pg/mL, a concentration probably not sufficient
to block IL-1 signaling but sufficient to limit its
spread from the source. A summary of cytokine inhib-
itors is shown in Table 3. The interactions of cyto-
kines with their receptors is discussed in the chapter
on Cytokine and receptor paradigm. Families of
receptors are illustrated in Figure 2.
The human genome comprises 3 Â10
9
bases of
DNA and estimates of the number genes range
between 50,000 and 100,000 (Schuler et al., 1996).
Thus it is not surprising that there is a tendency to use
the same messenger molecule (e.g. cytokine) and
receptor molecules, with their complex signaling hook-
ups for mediation of distinct messages in different
cells. Thus IL-1 was reported to be a `lymphocyte
activating factor' on T cells, as well as `catabolin',
a degradation-inducing factor on cartilage. The
different actions of a single cytokine on distinct cells
are sometimes known as `pleiotropy'. This process
maximizes information transfer while utilizing the
fewest possible genes (Feldmann et al., 1996a; Vilcek,
1998).
For certain important functions, such as macro-
phage activation, there appear to be multiple cyto-
kines capable of this function, all of which may be
present in apparently active concentration at times of
activation. This is known as `redundancy' in cytokine
function. An even more marked example is the
numerous chemokines that can attract monocytes for
example. It is likely that this functional redundancy
based on in vitro assays is more apparent than real.
Gene targeting (knockout) experiments have shown
unexpected differences between certain cytokines with
overlapping in vitro activities. This is presumably
based on in vivo compartmentalization, cytokine
interactions, and differences in the kinetics of
cytokine production and effects.
SOURCES OF CYTOKINES
Essentially all cells make cytokines, when stimulated.
Macrophages, T cells, and mast cells are among the
most abundant sources, but other cells of hemato-
poietic linage such as B cells, dendritic cells, and NK
cells are all important sources, as are nonhemato-
poietic cells such as fibroblasts, chondrocytes, hepato-
cytes, epithelial cells, etc.
For a period of time in the 1980s it was considered
that granulocytes did not make any cytokines nor did
dendritic cells. However, more refined technology has
shown that the cytokine production found in granulo-
cyte preparations was not due to contaminant macro-
phages, and even though each granulocyte may make
little compared with a macrophage, their huge
numbers in certain lesions means that the cytokines
released by granulocytes are of importance. This may
especially be the case for their release of CC chemo-
kines, which helps to orchestrate the subsequent
ingress of macrophages and T cells. The current con-
sensus is thus that all nucleated cells, including neurons
make cytokines. In the on-line version, cytokines
Figure 1 What are the differences between cytokines and hormones?
Cytokine
Acts locally
Made by many cells, e.g. IL-1, IL-6 almost ubiquitous
Synthesized transiently after cell activation
Usually inactive in serum/plasma
IL-6, M-CSF, EPO Hormone
Acts at distance
Made by specialized cells and organs, e.g. pituitary, adrenal
Produced constitutively and continuously
Bioactive in serum/plasma
Common properties: Receptors often homologous (e.g. hematopoietin)
Potent signals
Gradient
Introduction to the Role of Cytokines in Innate Host Defense and Adaptive Immunity 11
produced by different cell types are listed by choosing
the `cell type' view.
CYTOKINES IN BIOLOGICAL
PROCESSES
Cytokines are involved in growth, differentiation,
cell division, apoptosis, inflammation, immunity,
repair, fibrosis, etc. This is perhaps not surprising
considering the numbers of cytokines and growth
factors which have been described.
Hematopoiesis is a good example, with numerous
cytokines and hemotopoietic growth factors inter-
playing to permit the highly regulated and flexible
pattern of cell growth and differentiation, both in
health and in response to stress. To activate stem
cells, IL-1, IL-6, stem cell factor, and Flt-3 ligand
interact. If these cells are differentiating towards the
myeloid lineage, IL-3, G-CSF, M-CSF, and GM-CSF
will then become involved. Under the stimulation of
the entities (and probably others not yet known) a
single stem cell can repopulate the hematopoietic
system of a mouse, yielding millions of progeny in a
few weeks. This topic is discussed in the chapter on
Hematopoietic growth factors.
Numerous cytokines are also involved in wound
healing and repair. For example repair of skin
epithelium growth probably involves EGF and KGF,
the dermal tissue growth probably involves PDGF,
TGF, and FGF, new blood vessel formation and
repair probably involves VEGF and basic FGF, etc.
Thus in any biological process, a number of cytokines
are usually involved.
Inflammation
Cytokines are critical molecules in the induction and
resolution of inflammatory responses. There are
numerous so-called `proinflammatory cytokines', but
Table 3 Cytokine inhibitors
Inihibitors Examples
Soluble, extracellular domain of cytokine receptor sTNFR p55 and p75, sIL-1R types I and II,
sIFNR, sIL-6R, etc.
IL-1 receptor antagonist (IL-1Ra)
Cytokines with mostly inhibitory properties TGF, IL-10, IL-4, IL-13, IFN, and IFN
Low affinity
2
-Macroglobulin, ? albumin
Figure 2 Cytokine receptor families are grouped broadly into six categories
based on their molecular structure.
Hematopoietic
GF-R family
Ig
family
IFN-R
family
TNF/NGF-R
family
Type II
TGF β R
Transmembrane
IL-2Rβ
IL-3R
IL-4Rα
IL-5Rα
IL-6R
IL-7R
IL-9
IL-3β, IL-5
gp130
GM-CSFR
EPOR
G-CSFR
LIFR
CNTFR
IL-1R
CSF-1R
PDGFR
SCFR
IFNαR
IFNβR
IFNγ R
IL-10R
P55 TNFR
p75 TNFR
CD30
CD27
CD40
OX40
NGF R
Fas
4-1BB
Chemokine receptor
e.g. IL-8RA
IL-8RB
RANTES
Ig
Ig
Ig
12 Joost J. Oppenheim and Marc Feldmann
considerably fewer `anti-inflammatory cytokines'
known so far. The classic proinflammatory cytokines
include IL-1, TNF, IL-6, IL-12, GM-CSF, and
IFN, molecules that induce both acute and more
chronic inflammatory responses. Chemokines are also
major contributors to inflammation, being involved
in the chemotaxis of first neutrophils and subse-
quently macrophages, lymphocytes, eosinophils, etc.
Vascular changes in inflammation (e.g. neovascular-
ization) are also under cytokine regulation; vascular
endothelial growth factor (VEGF) was also discov-
ered as a major cause of capillary leak, known as
`vascular permeability factor' (Ferrara et al., 1991).
However, it is well known that there are many aspects
of inflammation which are not due to cytokines. The
immediate wheal and flare reaction has mediators,
e.g. histamine and bradykinin, which were described
before the cytokine field blossomed. Lipid mediators
such as prostaglandins are also of importance in acute
inflammation (Pettipher, 1998).
Injecting the proinflammatory cytokines such as
IL-1, TNF, IL-6, or IFN induces a variety of the
typical symptoms of infections. For example, IL-1,
TNF, and IL-6 induce fever and hypotension to
various degrees, IL-1, TNF, and IFN induce head-
ache, malaise, weakness. Interferons in particular give
rise to malaise, weakness, and lethargy which can be
debilitating in some patients being treated with
recombinant IFN, and interferes with compliance to
therapy.
Other cytokines are also of importance in inflam-
mation; these include those derived from T cells, such
as IL-2, LT, IL-4, and IL-10.
The importance of cytokines with anti-inflamma-
tory effects such as TGF and IL-10 in limiting the
magnitude and extent of inflammation is clearly
illustrated by the phenotypes of mice with inactiva-
tion of such cytokine genes. TGF1 knockouts become
ill within a week or two and die within 4 weeks of
birth. They develop leukocyte infiltration and inflam-
mation of many organs leading to death. IL-10
knockouts spontaneously develop an inflammatory
bowel disease with resemblance to Crohn's disease, if
they are not kept germ free. Both respond to irritants
and inducers of inflammation and delayed-type
hypersensitivity are markedly augmented, verifying
the importance of IL-10 in regulating both of these
responses (Berg et al., 1995).
The anti-inflammatory cytokines, IL-10, IL-4,
IL-13, and TGF and in some instances IL-11, act
in part by reducing the production of proinflamma-
tory cytokines from macrophages (IL-1, IL-12, IFN,
TNF, etc.), and they also suppress T cell production
of IL-2, IFN, and LT (Massague, 1987; Moore
et al., 1993).
Immunity
The immune response comprises two components,
innate immunity and acquired immunity, both of
which aim to limit the potential pathology induced by
bacteria, parasites, and viruses. Innate immunity
involves many factors such as complement, natural
antibodies, the function of abundant rapidly recruited
phagocytes such as neutrophilic granulocytes, macro-
phages and their antimicrobial products, such as
defensins, reactive oxygen species, and reactive nitro-
gen species such as NO. Cytokines are involved in
innate immunity with chemokines such as IL-8
involved in the recruitment and activation of neutro-
phils, others in the recruitment of macrophages. NK
cells as well as the phagocytes above respond to
microbial products with the production of cytokines.
In fact, microbial products such as LPS, products of
Corynebacterium parvum, and mycobacteria are
among the most powerful inducers of cytokines.
That certainly suggests that cytokines are important
in innate immunity.
Acquired immunity involves antigenic activation of
specifically reactive lymphocytes, and changes in
lymphocyte populations following antigen recogni-
tion, such as marked lymphocyte proliferation, anti-
body production and immunological memory. T
lymphocyte activation is orchestrated by numerous
cytokines, derived from antigen-presenting cells and T
cells. Of particular importance are IL-1 or IL-18
involved in the early events of induction of TH2 and
TH1 precursors respectively, IL-1, IL-6, and TNF
involved in upregulating IL-2 receptor expression, IL-
15 in initiating lymphocyte proliferation, IL-12 in
activation towards the TH1 phenotype, and IL-4 and
to a lesser extent IL-7 and IL-6 in promoting TH2
polarization. Together these cytokines are involved in
lymphocyte `costimulation'.
There is increasing evidence that some chemokines
released by dendritic cells and perhaps other antigen-
presenting cells (APCs) attract certain subsets of
lymphocytes, and facilitate the appropriate interac-
tions between APCs and T cells and subsequently
between T cells and B cells.
Cytokines released by activated T cells have con-
siderable effect on the subsequent development of the
adaptive immune response, acting on T cells, macro-
phages, B cells, etc. T cells are the major source of the
major T cell growth factors IL-2, IL-4, and IL-9 as
well as IFN and LT (Smith, 1988). IFN can alter
the development of subsets of T cells, augmenting
cytotoxic T cell functioning, concomitantly inhibiting
proallergic CD4‡ TH2 cells. Macrophage activation
is promoted by IFN, GM-CSF, and inhibited by
IL-4, IL-10, and IL-13 (Gordon, 1998). B cell
Introduction to the Role of Cytokines in Innate Host Defense and Adaptive Immunity 13
activation is augmented by IL-4, IL-6, IL-10, IL-13,
and IL-2; it tends to be inhibited by IFN. LT is vital
in the development of peripheral lymphoid tissues as
evidenced by the depleted lymph nodes and under-
developed spleens of LT knockout mice (De Togni
et al., 1994)
A unifying hypothesis has been proposed that
provides an attractive model for how these immuno-
regulatory cytokines modulate T cell and B cell
functions. Mosmann and Coffman first proposed the
existence of subsets of CD4‡ T cells that produce
distinct types of lymphokines (Mosmann et al., 1986;
reviewed by Street and Mossmann, 1991). They
reported that, upon stimulation, developmentally
immature naive T cells (THp) can only produce low
levels of IL-2. These THp cells develop into THo cells
which can be activated to produce low levels of a wide
variety of cytokines including IL-2, IFN, and IL-4.
Upon prolonged stimulation with appropriate anti-
gens and cytokines the THo subset polarize into
either CD4‡ TH1 cells that selectively produce IL-2,
IFN, and LT, which promote cell-mediated immu-
nity (CMI), or into TH2 cells that produce IL-4, IL-5,
IL-6, and IL-10, which promote antibody production
and humoral immunity. The cytokines produced by
these T cell subsets reciprocally regulate one another
since IFN inhibits the proliferation and functions of
TH2 cells, whereas the TH2 cell products, IL-4 and
IL-10, suppress cytokine production by both TH1
cells and monocytes.
Although these T cell subsets can be cloned and are
stable in vitro, they are not phenotypically distinct
and difficult to separate. Furthermore they are not
irreversibly differentiated, but can reverse their
cytokine production pattern. Identification of these
T cell subsets is retrospectively based on the identity
of their lymphokine products or potentially using cell
surface receptors, e.g. IL-12 receptor is downregu-
lated on TH2 cells. However, these distinctions are
becoming less clear since recent results indicate that
IL-10 is produced by human TH1 cells, TH2 cells,
and CD8‡ T cells as well as by B cells and monocytes
(Yssel et al., 1992). Furthermore, IL-12, a product of
monocytes and B cells, has a major impact in
promoting cell-mediated immunity, because IL-12
induces IFN and initiates the development of THo
into TH1 cells (Hsieh et al., 1992). Recently IL-6, in
an analogous fashion, has been identified as an
inducer of TH2 responses (Rincon et al., 1997).
Consequently, the phenotypic pedigree of the cells
producing these immunoregulatory cytokines should
be of less concern than the profile of participating
cytokines. The critical aspect of the hypothesis is that
`type 1 cytokines' such as IL-12 and IFN favor
cell-mediated immunity and actually interfere with the
induction of humoral immune responses. Conversely,
`type 2 cytokines' such as IL-4, IL-6, and IL-10 cause
immune deviation by suppressing the production of
CMI-inducing proinflammatory cytokines in favor
of the development of B cell-dependent antibody
responses (as reviewed by Oppenheim and Neta,
1994).
CYTOKINES CAN ACT IN
NETWORKS, CASCADES,
INTERACTIONS, ETC.
In any site of cell activation, with an inflammatory
and/or immune response, there are many cytokines
produced which will act on neighboring cells. These
cytokines are numerous, over 30 being known to be
present in the tissues of active rheumatoid arthritis
joints and in synovial fluid, for example (Feldmann
et al., 1997).
Many of these appear to mediate closely related
functions, and there would appear, at face value, to
be extensive `redundancy'. It would thus seem that
blocking any given function, say induction of
cartilage degradation, which is mediated by IL-1,
IL-1, TNF, and TNF/LT, may be difficult. All
these molecules may (in theory) need to be blocked to
diminish the cytokine-induced activation to suffi-
ciently low levels. That scenario would be the case if
all these molecules were independently regulated.
However there is now considerable evidence that in
an inflammatory/immune site, there is a `cytokine
network' or cascade, in which the actions of certain
cytokines are regulated by the activity of others.
The first clear example of this in human tissue was
found by investigating the proinflammatory cytokine
regulation in the rheumatoid synovium. This tissue
produces significant (i.e. bioactive) levels of IL-1,
IL-1, TNF, IL-6, IL-8, GM-CSF, etc. (reviewed in
Brennan et al., 1989; Feldmann et al., 1997). Evidence
for a `cytokine network' was obtained by the use of
neutralizing antibodies to TNF and the IL-1
receptor antagonist (IL-1Ra) in dissociated cultures
of rheumatoid synovium. These cultures produce high
levels of cytokines without extrinsic stimulation
and thus appear to reflect what is happening in the
synovium in vivo.
It was found that anti-TNF antibody reduced the
production of IL-1 (Brennan et al., 1989), IL-6, IL-8,
GM-CSF, whereas IL-1Ra reduced the production of
IL-6, IL-8, GM-CSF, but not of TNF, which led to
the notion of a network or cascade in these tissues
(Figure 3), with TNF at the apex followed by IL-1,
14 Joost J. Oppenheim and Marc Feldmann
and IL-8, IL-6, and GM-CSF downstream of both
TNF and IL-1 (Feldmann et al., 1997). There is also
evidence from the dissociated rheumatoid joint cell
cultures that anti-inflammatory mediators such as IL-
10, IL-1Ra, and soluble TNF receptors are regulated
by TNF and IL-11. A key question is whether such
networks or cascades operate in vivo. Confirmation of
this has come, for example, from clinical trials of anti-
TNF antibody in patients with active rheumatoid
arthritis, in which levels of IL-6, IL-8, IL-1Ra, and
soluble receptors are all diminished (Charles et al.,
1999).
It is likely that similar networks or cascades operate
in other conditions. For example in animal models of
sepsis (injected with LPS), it was reported that serum
levels of TNF precede those of IL-1 and IL-8,
suggesting the existence of a similar cascade. This
concept was supported by the effects of anti-TNF,
which reduced levels of IL-1 and IL-6 (Fong et al.,
1989) (Figure 4).
CYTOKINES REGULATE THE
ACUTE PHASE RESPONSE
The systemic and metabolic changes induced by a
marked local inflammatory response in which cyto-
kines spill over into the systemic circulation is known
as the acute phase response (Kushner, 1982; Gabay
and Kushner, 1999). Typical stresses giving rise to the
acute phase response include severe infection, burns,
trauma, and tissue damage and infarction. The acute
phase response includes fever, altered synthesis of
proteins by the liver (often termed acute phase
proteins) and changes in protein, lipid, and glucose
metabolism. Cytokines, especially IL-6, have been
shown to be important mediators of this response
(Fey and Gauldie, 1990; Fearon et al., 1991; Kushner,
1993; Gabay and Kushner, 1999).
The changes in serum plasma proteins reflect
changes in synthesis in the liver, as well as decreased
catabolism. The changes are in both directions, with
the greatest changes, up to 1000-fold increase in the
serum concentration of C reactive protein (CRP) and
serum amyloid A (SAA).
While it is likely that the elevated levels of acute
phase proteins are beneficial in the short term, it is
not necessarily the case in the long term. Fibrinogen is
a case in point; short term it may help tissue repair by
promoting the adhesion and spreading of cells, but
long-term high levels of fibrinogen predispose to
atherosclerosis and its complications (Ernst and
Resch, 1993; Farrell and al-Mondhiry, 1997).
IL-6 is not the only cytokine to influence the acute
phase protein response by the liver (Fearon et al.,
1991). In vitro, there are numerous cytokines which
can regulate hepatocytes. These include the other
members of the IL-6 `family', which use the same
signaling transduction molecules, namely oncostatin
M, LIF, and IL-11. Also effective in vitro, but less so
are IL-1 and TNF. Whether some of the latter
effects are secondary to IL-6 induction is not yet
clear.
In the response to infections and other numerous
agents which induce hepatic acute phase protein
responses there are also other systemic phenomena,
inducible experimentally by cytokines. Fever can be
induced by IL-1, IL-6, TNF, and IFN in rabbits.
Cytokines can also promote sleep, for example IL-1
and TNF. Anorexia is also a response to systemic
inflammatory states, and can be induced by IL-1 and
TNF. In the latter two examples it is intracerebral
cytokine that is especially important.
Anemia is a feature of chronic inflammation whose
mechanism is not well understood. IL-1, TNF, and
IL-6 all have effects which would be expected to
Figure 3 The cytokine cascade in rheumatoid
arthritis.
Anti-inflammatory
IL-10, IL-1Ra, sTNFR
TIMP-1, TIMP-2
Immune
system
TNFα IL-1
MMP-1, MMP-3
IL-6, IL-8, GM-CSF
Proinflammatory
Figure 4 Disequilibrium of cytokines and their inhibi-
tors in active rheumatoid arthritis. This concept explains
why pro- and anti-inflammatory aspects are upregulated
in rheumatoid arthritis.
Anti-inflammatory
Proinflammatory
TNF
IL-1
MMP-1
MMP-3
TGF β
sTNFR
IL-10
IL-1Ra
TIMP-1
TIMP-2
IL-11
Introduction to the Role of Cytokines in Innate Host Defense and Adaptive Immunity 15
reduce erythrocyte production. Definitive evidence
for a role of cytokines, especially TNF and IL-6, in
the anemia of chronic rheumatoid arthritis has been
provided by the relief of anemia after anti-TNF
therapy (Davis et al., 1997).
Cachexia is a state of hypercatabolism, especially of
lean body mass, which occurs in chronic infections,
especially with parasites, and in cancer. A number of
cytokines including TNF and IL-6 have been impli-
cated in this process (Beutler and Cerami, 1989;
Strassmann et al., 1992).
REGULATION OF CYTOKINE
EFFECTS
Cytokines provide potent and powerful signals. It is
thus evident that there must be a number of mech-
anisms for regulating and limiting their effects, to
reduce the potential for cytokine-induced pathology.
Synthesis and release
Typically, synthesis of cytokines is transient, and is
regulated transcriptionally. Cytokine genes are highly
inducible, and a number of transcription factors, such
as NFB, NF-AT, and AP-1 are involved in
regulating the production of the mRNAs (Rao et al.,
1997; Tsuruta et al., 1998). For some cytokines there
are also posttranscriptional regulatory events, with
the 3
0
untranslated region of many cytokine mRNAs
having an AU-rich region which functions to reduce
mRNA half-life and regulate expression in other ways
(Shaw and Kamen, 1986). An example is TNF,
whose expression is deregulated by deletion of this 3
0
untranslated region, leading to a variety of TNF-
dependent pathologies, chiefly arthritis and inflam-
matory bowel disease in transgenic mice (Pasparakis
et al., 1996). LPS inducibility of TNF in macro-
phages also depends on the 3
0
untranslated region.
The release of cytokines from cells is also subject to
regulation. Different ways of cytokine release exist.
Mast cells and platelets can release stored cytokines
by degranulation. A number of cytokines, including
IL-1, are released following cleavage of the proform;
for example for IL-1 and IL-18 by the IL-1-
converting enzyme, also known as caspase 1 or ICE
(Ghayur et al., 1997). TNF is initially membrane
bound, but is then cleaved by a membrane-bound
matrix metalloproteinase, known as TNF-convert-
ing enzyme or TACE, which is a member of the
ADAM family (Black et al., 1997).
Extracellular effects
Localization of cytokine effects to the site of pro-
duction is likely to be the usual mode and function,
especially where low amounts are produced. Many
cytokines bind to the extracellular matrix to proteo-
glycans, such as heparin sulfate (Novick et al., 1989).
If, however, large quantities are produced, these will
exhaust the capacity of local receptors to bind them,
and diffusion into blood and lymph becomes possible.
In the body fluids, extracellular as well as intravas-
cular, there are often also high concentrations of
soluble receptors to many cytokines (Novick et al.,
1989). These usually bind to and inhibit the cytokine
and this prevents function away from the source of
production (and highest concentration). An impor-
tant exception is the soluble IL-6 receptor, which acts
as a coagonist, and enables IL-6 to act as a plasma
hormone, which permits local inflammation to gen-
erate signals to the liver to produce the acute phase
proteins.
2
-Macroglobulin, present in the blood at
high concentrations, also binds a variety of cytokines.
Cytokines are cleared from the body in various
ways ± via kidney, liver, receptor-mediated endocy-
tosis, and perhaps via the skin; shed keratinocytes
contain a lot of cytokines.
Regulation of signaling
Little is known about how cytokine signaling is
limited in time. There are concentration threshold
effects for inducing signaling and competition for
signaling components intracellularly may occur.
However it is likely that there are families of signaling
inhibitors. One such family is variously termed CIS1
(cytokine-inducible SH2-containing protein), SOCS
(suppressor of cytokine signaling), SSI-1 (STAT-
induced STAT inhibitor), and JAB (JAK-binding
protein) (Aman and Leonard, 1997). There are cur-
rently eight known members of this family, which are
structurally related with a characteristic domain.
These regulate multiple cytokines. For example SSI-1
interacts with all four JAK kinases and inhibits, but
CIS1 acts differently, inhibiting receptor-induced
STAT5 induction (Naka et al., 1998), IL-6, IL-2,
IL-3, IFN as well as growth hormone.
Cytokine synthesis inhibitors
During periods of stress, levels of endogenous inhib-
itors are increased. These include corticosteroids,
which inhibit a wide spectrum of proinflammatory
16 Joost J. Oppenheim and Marc Feldmann
cytokines, probably chiefly by diminishing the effects
of NFB. The exact molecular mechanism of this re-
mains controversial (Dumont et al., 1998). Adrenergic
agents which increase intracellular levels of cyclic
AMP (cAMP) such as phosphodexterase inhibitors
may also limit the release of proinflammatory cyto-
kines, including TNF and IL-12. Prostaglandins
also elevate cAMP and have the same consequences
(Kunkel et al., 1988; Van der Pouw Kraan et al.,
1995).
Cytokines such as IL-10, TGF, IL-4, and IL-13
have widespread inhibitory effects in the synthesis of
proinflammatory cytokines from macrophages.
References
Aman, M. J., and Leonard, W. J. (1997). Cytokine signaling:
cytokine-inducible signaling inhibitors. Curr. Biol. 7, 784±788.
Andus, T., Geiger, T., Hirano, T., Kishimoto, T., and
Heinrich, P. C. (1988). Action of recombinant human interleu-
kin 6, interleukin 1 beta and tumor necrosis factor alpha on the
mRNA induction of acute-phase proteins. Eur. J. Immunol. 18,
739±746.
Arend, W. P. (1993). Interleukin-1 receptor antagonist. Adv.
Immunol. 54, 167±227.
Bain, M. L., Vas, M., and Lowenstein, L. (1964). The development
of large immature mononuclear cells in mixed leukocyte cul-
tures. Blood 23, 108.
Bennett, I. L. Jr., and Beeson P. B. (1953). Studies on the patho-
genesis of fever: II: Characterization of fever-producing sub-
stances from polymorphonuclear leukocytes and from the
fluid of sterile exudates. J. Exp. Med. 98, 493±508.
Berg, D. J., Leach, M. W., Kuhn, R., Rajewsky, K., Muller, W.,
Davidson, N. J., and Rennick, D. (1995). Interleukin 10 but not
interleukin 4 is a natural suppressant of cutaneous inflamma-
tory responses. J. Exp. Med. 182, 99±108.
Bernhagen, J., Calandra, T., Michell, R. A., Martin, S. B.,
Tracey, K. J., Voelter, W., Manogue, K. R., Cerami, A., and
Bucala, R. (1993). MIF is a pituitary-derived cytokine that
potentiates lethal endotoxaemia. Nature 365, 756±759.
Beutler, B., and Cerami, A. (1989). The biology of cachectin/
TNF ± a primary mediator of the host response. Annu. Rev.
Immunol. 7, 625±655.
Black, R. A., Rauch, C. T., Kozlosky, C. J., Peschon, J. J.,
Slack, J. L., Wolfson, M. F., Castner, B. J., Stocking, K. L.,
Reddy, P., Srinivasan, S., Nelson, N., Boiani, N., Schooley, K. A.,
Gerhart, M., Davis, R., Fitzner, J. N., Johnson, R. S.,
Paxton, R. J., March, C. J., and Cerretti, D. P. (1997). A metal-
loproteinase disintegrin that releases tumour-necrosis factor
alpha from cells. Nature 385, 729±733.
Bloom, B. R., and Bennett, B. (1966). Mechanism of a reaction
in vitro associated with delayed-type hypersensitivity. Science
153, 80±82.
Brennan, F. M., Chantry, D., Jackson, A., Maini, R., and
Feldmann, M. (1989). Inhibitory effect of TNF antibodies
on synovial cell interleukin-1 production in rheumatoid arthri-
tis. Lancet ii, 224±247.
Carswell, E. A., Old, L. J., Kassel, R. L., Green, S., Fiore, N., and
Williamson, G. (1975). An endotoxin induced serum factor that
causes necrosis of tumors. Proc. Natl Acad. Sci. USA 72, 3666.
Charles, P., Elliott, M. J., Davis, D., Potter, A., Kalden, J. R.,
Antoni, C., Breedveld, F. C., Smolen, J. S., Eberl, G., Woody, J. N.,
Feldmann, M., and Maini, R. N. (1999). Regulation of cyto-
kines and acute phase proteins following TNF blockade in
rheumatoid arthritis. J. Immunol. 163, 1521±1528.
Cohen, S., Bigazzi, P. E., and Yoshida, T. (1974). Similarities of T
cell function in cell-mediated immunity and antibody produc-
tion. Cell. Immunol. 12, 150±159.
Content, J., De Wit, L., Pierard, D., Derynck, R., De Clercq, F.,
and Fiers, W. (1982). Secretory proteins induced in human
fibroblasts under conditions used for the production of inter-
feron beta. Proc. Natl Acad. Sci. USA 79, 2768.
David, J. R. (1966). Delayed hypersensitivity in vitro: its mediation
by cell-free substances formed by lymphoid cell-antigen interac-
tion. Proc. Natl Acad. Sci. USA 56, 73±77.
Davis, D., Charles, P. J., Potter, A., Feldmann, M., Maini, R. N.,
and Elliott, M. J. (1997). Anaemia of chronic disease in rheu-
matoid arthritis: in vivo effects of tumour necrosis factor
blockade. Br. J. Rheumatol. 36, 950±956.
Derynck, R., Jarrett, J. A., Chen, E. Y., Eaton, D. H., Bell, J. R.,
Assoian, R. K., Roberts, A. B., Sportn, M. B., and
Goeddel, D. V. (1985). Human transforming growth factor-
beta complementary DNA sequence and expression in normal
and transformed cells. Nature 316, 701±705.
De Togni, P., Goellner, J., Ruddle, N. H., Streeter, P. R., Fick, A.,
Mariathasan, S., Smith, S. C., Carlson, R., Shornick, L. P.,
Strauss-Schoenberger, J., Russell, J. H., Karr, R., and
Chaplin, D. D. (1994). Abnormal development of peripheral
lymphoid organs in mice deficient in lymphotoxin. Science
264, 703±707.
Dinarello, C. A. (1998). In ``The Cytokine Handbook'' (ed
A. W. Thomson), Interleukin-1, pp. 36±72. Academic Press,
New York.
DiSanto, J. P., Muller, W., Guy-Grand, D., Fischer, A., and
Rajewsky, K. (1995). Lymphoid development in mice with a
targeted deletion of the interleukin 2 receptor chain. Proc.
Natl Acad. Sci USA 92, 377±381.
Dumonde, D. C., Wolstencroft, R. A., Panayi, G. S., Matthew, M.,
Morley, J., and Howson, W. T. (1969). Lymphokines: non-anti-
body mediators of cellular immunity generated by lymphocyte
activation. Nature 224, 38±42.
Dumont, A., Hehner, S. P., Schmitz, M. L., Gustafsson, J. A.,
Liden, J., Okret, S., van der Saag, P. T., Wissink, S., van der
Burg, B., Herrlich, P., Haegeman, G., De Bosscher, K., and
Fiers, W. (1998). Cross-talk between steroids and NF-kappa
B: what language? Trends Biochem. Sci. 23, 233±235.
Durum, S. K., and Muegge, K. (1998). In ``Cytokine Knockouts.''
Humana Press, Totowa, New Jersey.
Ernst, E., and Resch, K. L. (1993). Fibrinogen as a cardiovascular
risk factor: a meta-analysis and review of the literature. Ann.
Intern. Med. 118, pp. 956±963.
Farrell, D. H., and al-Mondhiry, H. A. (1997). Human fibroblast
adhesion to fibrinogen. Biochemistry 36, 1123±1128.
Fearon, K. C. H., McMillan, D. C., Preston, T., Winstanley, F. P.,
Cruickshank, A. M., and Shenkin, A. (1991). Elevated circulat-
ing interleukin-6 is associated with an acute-phase response but
reduced fixed hepatic protein synthesis in patients with cancer.
Ann. Surg. 213, 26±31.
Feldmann, M., Brennan, F. M., and Maini, R. N. (1996a). Role
of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14,
397±440.
Feldmann, M., Dower, S., and Brennan, F. M. (1996b). In
``Cytokines in Autoimmunity'' (ed F. M. Brennan and
M. Feldmann), The role of cytokines in normal and pathologi-
cal situations, pp. 1±24. R. G. Landes & Co., Austin, TX.
Feldmann, M., Elliott, M. J., Woody, J. N., and Maini, R. N.
(1997). Anti tumour necrosis factor therapy of rheumatoid
arthritis. Adv. Immunol. 64, 283±350.
Introduction to the Role of Cytokines in Innate Host Defense and Adaptive Immunity 17
Fernandez-Botran, R. (1991). Soluble cytokine receptors: their
role in immunoregulation. FASEB J. 5, 2567±2574.
Ferrara, N., Houck, K. A., Jakeman, L. B., Winer, J., and
Leung, D. W. (1991). The vascular endothelial growth factor
family of polypeptides. J. Cell Biochem. 47, 211±218.
Fey, G. H., and Gauldie, J. (1990). The acute phase response of
the liver in inflammation. Prog. Liver Dis. 9, 89±116.
Fong, Y., Tracey, K. J., Moldawer, L. L., Hesse, D. G.,
Manogue, K. B., Kenney, J. S., Lee, A. T., Kuo, G. C.,
Allison, A. C., Lowry, S. F., and Cerami, A. (1989). Antibodies
to cachectin/tumor necrosis factor reduce interleukin 1 and
interleukin 6 appearance during lethal bacteremia. J. Exp. Med.
170, 1627±1633.
Gabay, C., and Kushner, I. (1999). Acute-phase proteins and
other systemic responses to inflammation. N. Engl. J. Med.
340, 448±454.
Gery, I., and Waksman, B. H. (1972). Potentiation of lymphocyte
responses to mitogens. II. The cellular source of potentiating
mediators. J. Exp. Med. 136, 143±155.
Gery, I., Gershon, R. K., and Waksman, B. H. (1971).
Potentiation of cultured mouse thymocyte responses by factors
released by peripheral leucocytes. J. Immunol. 107, 1778±1780.
Ghayur, T., Banerjee, S., Hugunin, M., Butler, D., Herzog, L.,
Carter, A., Quintal, L., Sekut, L., Talanian, R., Paskind, M.,
Wong, W., Kamen, R., Tracey, D., and Allen, H. (1997).
Caspase-1 processes IFN-gamma-inducing factor and regulates
LPs-induced IFN-gamma production. Nature 386, 619±623.
Gordon, J., and MacLean, L. D. (1965). A lymphocyte-stimulat-
ing factor produced in vitro. Nature 208, 795.
Gordon, S. (1998). In ``Encyclopedia of Immunology'' (ed
P. J. Delves and I. M. Roitt), Macrophage activation, pp.
1642±1649. Academic Press, London.
Gowans, J. L. (1959). The recirculation of lymphocytes from
blood to lymph in the rat. J. Physiol. 146, 54±69.
Granger, G. A., and Williams, T. W. (1968). Lymphocyte cyto-
toxicity in vitro: activation and release of a cytotoxic factor.
Nature 218, 1253±1254.
Gray, P. W., Leung, D. W., Pennica, D., Yelverton, E.,
Najarian, R., Simonsen, C. C., Derynck, R., Sherwood, P. J.,
Wallace, D. M., Berger, S. L., Levinson, A. D., and
Goeddel, D. V. (1982). Expression of human immune interferon
cDNA in E. coli and monkey cells. Nature 285, 503.
Gray, P., Aggarwal, B. B., Benton, C. V., Bringman, T. S.,
Hensel, W. J., Jarrett, J. A., Leung, D. W., Moffet, B.,
Ng, P., Svedersky, L. P., Palladino, M. A., and Nedwin, G. R.
(1984). Cloning and expression of cDNA for human lympho-
toxin, a lymphokine with tumor necrosis activity. Nature
312, 721.
Hirano, T., Yasukawa, K., Harada, H., Taga, T., Watanabe, Y.,
Matsuda, T., Kashiwamura, S., Nakajima, K., Koyama, K.,
Iwamatsu, A., Tsunasawa, S., Sakayama, F., Matsui, H.,
Takahara, Y., Taniguchi, T., and Kishimoto, T. (1986).
Complementary DNA for a novel human interleukin (BSF-2)
that induces B lymphocytes to produce immunoglobulin.
Nature 324, 73.
Hsieh, G. S., Macatonia, S. E., Tripp, C. S., Wolf, S. F.,
O'Garra, A., and Murphy, K. M. (1992). Listeria induced
TH1 development in TCR transgenic CD4‡ T cells occurs
through macrophage production of IL-12. Science 260, 547±
549.
Ihle, J. N., Pepersack, L., and Rebar, L. (1981). Regulation of T
cell differentiation: In vitro induction of 20 hydroxysteroid
dehydrogenase in splenic lymphocytes from athymic mice by a
unique lymphokine. J. Immunol. 126, 2184.
Isaacs, A., and Lindenmann, J. (1957). Virus interference. I.
Interferons. Proc. R Soc. Lond. B 147, 258.
Kasakura, S., and Lowenstein, L. (1965). A factor stimulating
DNA synthesis derived from the medium of leucocyte cultures.
Nature 208, 794±795.
Kasakura, S., and Lowenstein, L. (1967). DNA and RNA synth-
esis and the formation of blastogenic factor in mixed leucocyte
cultures. Nature 215, 80±81.
Kriegler, M., Perez, C., DeFay, K., Albert, I., and Lu, S. D.
(1988). A novel form of TNF/cachectin is a cell surface cyto-
toxic transmembrane protein: ramifications for the complex
physiology of TNF. Cell 53, 45±53.
Kunkel, S. L., Spengler, M., May, M. A., Spengler, R., Larrick, J.,
and Remick, D. (1988). Prostaglandin E2 regulates macro-
phage-derived tumor necrosis factor gene expression. J. Biol.
Chem. 263, 5380±5384.
Kushner, I. (1982). The phenomenon of the acute phase response.
Ann. N.Y. Acad. Sci. 389, 39±48.
Kushner, I. (1993). In ``Clinical Applications of Cytokines. Role in
Pathogenesis Diagnosis and Therapy'' (ed J. J. Oppenheim,
J. L. Rosso, and A. J. H. Gearing) Regulation of the acute
phase response by cytokines, pp. 27±34. Oxford University
Press, Oxford.
Larsen, C. G., Anderson, A. O., Appella, E., Oppenheim, J. J.,
and Matsushima, K. (1989). Identity of chemotactic cytokine
for T-lymphocytes with neutrophil activating protein (NAP-1):
A candidate interleukin 8. Science 243, 1464±1466.
Leonard, W. J., Depper, J. M., Crabtree, G. R., Rudikoff, S.,
Pumphrey, J., Robb, R. J., Kronke, M., Svetlik, P. B.,
Pfeffer, N. J., Waldmann, T. A., and Green, W. C. (1984).
Molecular cloning and expression of cDNAs for the human
interleukin-2 receptor. Nature 311, 626.
Levi-Montalcini, R., and Hamburger, V. (1953). A diffusible agent
of mouse sarcoma producing hyperplasia of sympathetic gang-
lia and hyperneurotization of the chick embryo. J. Exp. Zool.
123, 233±388.
Luger, T. A., Charon, J. A., Colot, M., Miksche, M., and
Oppenheim, J. J. (1983). Chemotactic properties of partially
purified human epidermal cell-derived thymocyte activating
factor CETAF for polymorphonuclear and mononuclear cells.
J. Immunol. 13, 816±820.
Massague, J. (1987). The TGF1 family of growth and differen-
tiation factors. Cell 49, 437±438.
Matsushima, K., Morishita, K., Yoshimura, T., Lavu, S.,
Kobayashi, Y., Lew, W., Appella, E., Kung, H. F., Leonard, E.,
and Oppenheim, J. J. (1988). Molecular cloning of cDNA for
a human monocyte derived neutrophil chemotactic factor
(MDNCF) and the induction of MDNCF mRNA by interleu-
kin 1 and tumor necrosis factor. J. Exp. Med. 167, 1883±1893.
Menkin, V. (1944). Chemical basis of fever. Science 100, 337±338.
Miyajima, A., Kitamura, T., Harada, N., Yokota, T., and
Arai, K.-I. (1992). Cytokine receptors and signal transduction.
Annu. Rev. Immunol. 10, 298±332.
Mizel, S. B., and Farrar, J. J. (1970). Revised nomenclature for
antigen non-specific T cell proliferation and helper factors. Cell.
Immunol. 48, 433±436.
Moore, K., Viera, P., Fiorentino, D. F., Troustine, M. L.,
Khan, T. A., and Mosmann, T. R. (1990). Homology of cyto-
kine synthesin inhibitory factor (IL-10) to Epstein-Barr virus
gene BCRF1. Science 248, 1230±1234.
Moore, K. W., O'Garra, A., de Waal Malefyt, R., Vieira, P., and
Mosmann, T. R. (1993). Interleukin-10. Annu. Rev. Immunol.
11, 165±190.
Morgan, D. A., Ruscetti, F. W., and Gallo, R. (1976). Selective
in vitro growth of T lymphocytes from normal human bone
marrows. Science 193, 1007.
Mosmann, T. R., Cherwinski, H., Bond, M. W., Giedlin, M. A.,
and Coffman, R. L. (1986). Two types of murine helper T cell
18 Joost J. Oppenheim and Marc Feldmann
clone. I. Definition according to profiles of lymphokine activ-
ities and secreted proteins. J. Immunol. 136, 2348±2357.
Nagata, S. (1997). Apoptosis by death factor. Cell 88, 355±365.
Nagata, S., and Golstein, P. (1995). The Fas death factor. Science
267, 1449±1456.
Nagata, S., Taira, H., Hall, A., Johnsrud, H., Streuli, M.,
Escodi, J., Boll, W., Cantell, K., and Weissmann, C. (1980).
Synthesis in E. coli of a polypeptide with human leukocyte
interferon activity. Nature 284, 316.
Naka, T., Matsumoto, T., Narazaki, M., Fujimoto, M.,
Morita, Y., Ohsawa, Y., Saito, H., Nagasawa, T., Uchiyama, Y.,
and Kishimoto, T. (1998). Accelerated apoptosis of lympho-
cytes by augmented induction of Bax in SSI-1(STAT-induced
STAT inhibitor-1) deficient mice. Proc. Natl Acad. Sci USA 95,
15577±15582.
Nathan, C. F., Karnovksy, M. L., and David, J. R. (1971).
Alterations of macrophage functions by mediators from lym-
phocytes. J. Exp. Med. 133, 1356±1376.
Novick, D., Englemann, H., Wallach, D., and Rubinstein, M.
(1989). Soluble cytokine receptors are present in normal
human murine. J. Exp. Med. 170, 1409±1414.
Nowell, P. C. (1960). Phytohemaglutinin: an imitator of mitosis in
cultures of normal human leukocytes. Cancer Res. 20, 462.
Oppenheim, J. J., and Gery, I. (1982). Interleukin 1 is more than
an interleukin. Immunol. Today 3, 113±119.
Oppenheim, J. J., and Gery, I. (1993). From lymphodrek to IL 1.
Immunol. Today 14, 232±234.
Oppenheim, J. J., and Neta, R. (1994). Pathophysiological roles of
cytokines in development, immunity and inflammation. FASEB
J. 8, 158±162.
Oppenheim, J. J., and Saklatvala, J. (1993). ``Clinical Applications
of Cytokines'' (ed J. J. Oppenheim, J. L. Rossio, and
A. J. H. Gearing), Cytokines and their receptors, 3±15.
Oxford University Press, New York.
Oppenheim, J. J., Rossio, J. L., and Gearing, A. J. H. (1993).
``Clinical Applications of Cytokines''. Oxford University Press,
New York.
Ortaldo, J. R. M., Mason, A. T., Gerard, J. P., Henderson, L. E.,
Farrar, W., Hopkins, R. F., Herberman, R. B., and Rabin, H.
(1984). Effects of natural and recombinant IL 2 on regulation of
IFN production and natural killer cell activity. J. Immunol.
133, 779±783.
Pasparakis, M., Alexopoulou, L., Douni, E., and Kollias, G.
(1996). Tumour necrosis factors in immune regulation, every-
thing that's interesting is...new! Cytokine Growth Factor Rev. 7,
223±229.
Pearmain G., Lycette R. R., and Fitzgerald P. H. (1963).
Tuberculin induced mitosis in peripheral blood leucocytes.
Lancet i, 637±638.
Pennica, D., Nedwin, G. E., Hayflick, J. S., Seeburg, P. H.,
Derynck, R., Palladino, M. A., Kohr, W. J., Aggarwal, B. B.,
and Goeddel, D. V. (1984). Human tumor necrosis factor, pre-
cursor structure, expression and homology to lymphotoxin.
Nature 312, 724.
Pettipher, E. R. (1998). In ``Encyclopedia of Immunology'' (ed
P. J. Delves and I. M. Roitt), Prostaglandins, pp. 2024±2027.
Academic Press, London.
Poupart, P., Vandenabeele, P., Cayphas, S., Van Snick, J.,
Haegeman, G., Kruys, V., Fiers, W., Content, J., Volckaert, C.,
Derynck, R., and Tavernier, J. (1987). B cell growth modulat-
ing and differentiating activity of recombinant human 26-kd
protein (BSF-2, HuIFN-beta 2, HPGF). EMBO J. 6, 1219±
1224.
Rao, A., Luo, C., and Hogan, P. G. (1997). Transcription factors
of the NFAT family: regulation and function. Annu. Rev.
Immunol. 15, 707±747.
Rincon, M., Anguita, J., Nakamura, T., Fikrig, E., and
Flavell, R. A. (1997). Interleukin (IL)-6 directs the differen-
tiation of IL-4 producing CD4‡ T cells. J. Exp Med. 185,
461±469.
Rosenwasser, L. J., Dinarello, C. A., and Rosenthal, A. S. (1979).
Adherent cell function in murine T lymphocyte antigen recogni-
tion. IV Enhancement of murine T-cell antigen recognition by
human leukocytic pyrogen. J. Exp. Med. 150, 70±79.
Ruddle, N. H., and Waksman, B. H. (1967). Cytotoxic effect of
lymphocyte-antigen interaction in delayed hypersensitivity.
Science 157, 1060±1062.
Sauder, D. N., Mounessa, N. L., Katz, S. I., Dinarello, C. A., and
Gallin, J. I. (1984). Chemotactic cytokines. The role of leuko-
cyte pyrogen and ETAF in neutrophil chemotaxis. J. Immunol.
132, 828±832.
Schorle, H., Holtschke, T., Hunig, T., Schimpl, A., and Horak, I.
(1991). Development and function of T cells in mice rendered
interleukin-2 deficient by gene targeting. Nature 352, 3621.
Schreiber, R. D., and Celada, A. (1985). In ``Lymphokines, Vol.
11'' (ed E. Pick), Molecular characterization of interferon as
a macrophage activating factor, pp. 87±118. Academic Press,
New York.
Schuler, G. D., Boguski, M. S., Stewart, E. A., Stein, L. D.,
Gyapay, G., Rice, K., White, R. E., Rodriguez-Tome, P.,
Aggarwal, A., Bajorek, E., Bentolila, S., Birren, B. B.,
Butler, A., Castle, A. B., Chiannilkulchai, N., Chu, A.,
Clee, C., Cowles, S., Day, P. J., Dibling, T., Drouot, N.,
Dunham, I., Duprat, S., East, C., and Hudson, T. J. (1996).
A gene map of the human genome. Science 274, 540±546.
Shaw, G., and Kamen, R. (1986). A conserved AU sequence from
the 3
0
untranslated region of GM-CSF mRNA mediates selec-
tive mRNA degradation. Cell 46, 659.
Smith, C. A., Farrah, T., and Goodwin, R. G. (1994). The TNF
receptor superfamily of cellular and viral proteins: activation,
costimulation, and death. Cell 76, 959±962.
Smith, K. A. (1988). Interleukin-2: inception, impact and implica-
tions. Science 240, 1169±1176.
Strassmann, G., Fong, M., Kenney, J. S., and Jacob, C. O. (1992).
Evidence for the involvement of interleukin 6 in experimental
cancer cachexia. J. Clin. Invest. 89, 1681±1684.
Street, N. E., and Mosmann, T. R. (1991). Functional diversity of
T lymphocytes due to secretion of different cytokine patterns.
FASEB J. 5, 171±177.
Taga, T., and Kishimoto, T. (1997). GP130 and the interleukin-6
family of cytokines. Annu. Rev. Immunol. 15, 797±819.
Taniguchi, T., Ohno, S., Fuji-Kuriyama, Y., and Muratmatsu, M.
(1980). The nucleotide sequence of human fibroblast interferon
cDNA. Gene 10, 11.
Taniguchi, T., Matsui, H., Fujita, T., Takaoka, C., Kashima, N.,
Yoshimoto, R., and Hamuro, J. (1983). Structure and expres-
sion of a cloned cDNA for human interleukin-2. Nature 302,
305.
Tsuruta, L., Arai, N., and Arai, K. (1998). Transcriptional control
of cytokine genes. Int. Rev. Immunol. 16, 581±616.
Van der Pouw Kraan, T. C., Boeije, L. C., Smeenk, R. J.,
Wijdenes, J., and Aarden, L. A. (1995). Prostaglandin-E2 is a
potent inhibitor of human interleukin 12 production. J. Exp.
Med. 181, 775±779.
Vilcek, J. (1998). In ``The Cytokine Handbook'' (ed
A. W. Thomson), The cytokines: an overview, pp. 1±20.
Academic Press, New York.
Waksman, B. H. (1978). Modulation of immunity by soluble med-
iators. Pharmac. Ther. A 2, 623±672.
Ward, P. A., Remold, H. G., and David, J. R. (1969). Leukotactic
factor produced by sensitized lymphocytes. Science 163, 1079±
1081.
Introduction to the Role of Cytokines in Innate Host Defense and Adaptive Immunity 19
Weiser, W. Y., Temple, T. A., Witek-Giannotti, J. S., Remold, H. G.,
Clark, C. C., and David, J. R. (1989). Molecular cloning of
cDNA encoding a human microphage migration inhibitory
factor. Proc. Natl Acad. Sci. USA 86, 7522±7526.
Yoshimura, T., Matsushima, K., Tanaka, S., Robinson, E. A.,
Appella, E., Oppenheim, J. J., and Leonard, E. J. (1987).
Purification of human monocyte-derived neutrophil chemotac-
tic factor that shares sequence homology with other host
defense cytokines. Proc. Natl Acad. Sci. USA 84, 9233±9237.
Yssel, H., DeWaal, M. R., Roncarolo, M.-G., Abrams, J. S.,
Kahesman, R., Spits, H., and DeVries, J. E. (1992). IL-10 is
produced by subsets of human CD4‡ T cell clones and periphe-
ral blood T cells. J. Immunol. 149, 2378±2384.
Zilberstein, A., Ruggieri, R., Korn, J. H., and Revel, M. (1986).
Structure and expression of cDNA and genes for human inter-
feron-beta-2, a distinct species inducible by growth-stimulatory
cytokines. EMBO J. 5, 2529.
Zubler, R. M., Lowenthal, J. W., Erard, F., Hashimoto, N.,
Devos, R., and MacDonald, H. R. (1984). Activated B cells
express receptors for and proliferate in response to pure IL-2.
J. Exp. Med. 160, 1170±1183.
20 Joost J. Oppenheim and Marc Feldmann