2. Cytokines and chemokines
Larry C. Borish, MD, and John W. Steinke, PhD Charlottesville, Va
Cytokines and chemokines are redundant secreted proteins
Abbreviations used
with growth, differentiation, and activation functions that reg-
ADCC: Antibody-dependent cellular cytotoxicity
ulate and determine the nature of immune responses and con-
AHR: Airway hyperreactivity
trol immune cell trafficking and the cellular arrangement of
APC: Antigen-presenting cells
immune organs. Which cytokines are produced in response to
GCSF: Granulocyte-colony stimulating factor
an immune insult determines initially whether an immune
ICAM: Intercellular adhesion molecule
response develops and subsequently whether that response is
ICE: Interleukin-1 converting enzyme
cytotoxic, humoral, cell-mediated, or allergic. A cascade of
IFN: Interferon
responses can be seen in response to cytokines, and often sev-
IL: Interleukin
eral cytokines are required to synergize to express optimal
LPS: Lipopolysaccharide
function. An additional confounding variable in dissecting
MAPK: Mitogen-activated protein kinase
cytokine function is that each cytokine may have a completely
NK: Natural killer
different function, depending on the cellular source, target,
SCF: Stem cell factor
and, most important, specific phase of the immune response
TGF-²: Transforming growth factor beta
during which it is presented. Numerous cytokines have both
TNF: Tumor necrosis factor
proinflammatory and anti-inflammatory potential; which
Tr: T repressor
activity is observed depends on the immune cells present and
VCAM: Vascular cell adhesion molecule
their state of responsiveness to the cytokine. For this chapter,
cytokines are grouped according to those that are mononu-
clear phagocytic derived or T-lymphocytic derived; that
mediate cytotoxic (antiviral and anticancer), humoral, cell-
mediated, or allergic immunity; and that are immunosuppres-
particularly effective in promoting the cellular infiltrate
sive. The biology of chemokines are then reviewed, grouped by
and damage to resident tissue characteristic of inflamma-
family. (J Allergy Clin Immunol 2003;111:S460-75.)
tion. The processing of antigens as they are taken up by
Key words: Allergy, colony-stimulating factors, cytokines,
APCs, processed, and presented to T-helper lymphocytes
chemokines, chemotaxis, IgE, mast cells, mononuclear phago-
provides one pathway for this class of cytokine produc-
cytes, T lymphocytes
tion. Alternatively, monocytes are potently triggered to
Cytokines are involved in virtually every facet of produce cytokines through the innate immune system,
immunity and inflammation, including innate immunity, using pattern recognition receptors that recognize stereo-
antigen presentation, bone marrow differentiation, cellu- typic components of pathogens that do not occur on
lar recruitment and activation, and adhesion molecule mammalian cells. These receptors, such as the
expression (Fig 1). Which cytokines are produced in lipopolysaccharide (LPS) receptor, contribute to the abil-
response to an immune insult determines initially ity of the immune system to distinguish pathogens from
whether an immune response develops and subsequently nonpathogenic proteins to which the immune system may
whether that response is cytotoxic, humoral, cell-mediat- become exposed. The cytokines predominantly produced
ed, or allergic. For presentation in this review, cytokines by monocytes include tumor necrosis factor (TNF), and
are grouped according to those that are predominantly several interleukin (IL) molecules known as IL-1, IL-6,
mononuclear phagocytic derived or T-lymphocyte IL-8, IL-12, IL-15, IL-18, and IL-23. IL-8 is also classi-
derived; those that predominantly mediate cytotoxic fied as a chemokine known as CXCL8; it and other
(antiviral and anticancer), humoral, cell-mediated, or chemokines are also secreted by APCs.
allergic immunity; and those that are immunosuppressive.
TUMOR NECROSIS FACTOR
CYTOKINE PRODUCTION BY ANTIGEN-
PRESENTING CELLS TNF represents two homologous proteins primarily
derived from mononuclear phagocytes (TNF-Ä…) and
Cytokines primarily derived from mononuclear phago- lymphocytes (TNF-²).1 The active form of both
cytic cells and other antigen-presenting cells (APCs) are cytokines is a homotrimer. In addition to mononuclear
phagocytes, TNF-Ä… may be produced by neutrophils,
activated lymphocytes, natural killer (NK) cells,
From the University of Virginia Health System, Beirne Carter Center for
endothelial cells, and mast cells. The most potent induc-
Immunology, Asthma and Allergic Disease Center, Charlottesville, Va.
Reprint requests: John W. Steinke, PhD, University of Virginia Health Sys- er of TNF by monocytes is LPS, acting through toll-like
tem, Beirne Carter Center for Immunology, Asthma and Allergic Disease
receptor 2 (TLR2) and TLR4. The toll-like receptors
Center, Charlottesville, VA 22908-1355.
(Table I) represent a family of pattern recognition recep-
© 2003 by Mosby, Inc. All rights reserved.
tors that recognize motifs used by pathogens but not
0091-6749/2003 $30.00 +0
doi:10.1067/mai.2003.108 mammalian cells and are capable of potently activating
S460
J ALLERGY CLIN IMMUNOL Borish and Steinke S461
VOLUME 111, NUMBER 2
FIG 1. Summary of actions of cytokines and chemokines. Cytokines derived predominantly from mononu-
clear phagocytic cells are uniquely important in innate immunity and both initiate immune responses and
generate symptoms associated with infections and inflammatory disorders. Phenotype of the subsequent
immune response is a function of the repertoire of cytokines produced by the responding T-helper lympho-
cytes. TH1-like lymphocytes are characterized by their production of IFN-Å‚ and primarily contribute to cellular
immunity. TH2-like lymphocytes are characterized by their production of IL-4, IL-5, IL-9, and IL-13 and con-
tribute to humoral and allergic responses. TH3-like lymphocytes have immunosuppressive tendencies and
are characterized by their production of IL-10 and TGF-².
innate immune responses, including mononuclear phago- mor immunity through direct cytotoxic effects on can-
cytic cell cytokine production. TNF-Ä… is processed as a cerous cells and by stimulating antitumor immune
membrane-bound protein from which the soluble active responses. TNF interacts with endothelial cells to induce
factor is derived by cleavage using the TNF-Ä… converting adhesion molecules known as intracellular adhesion mol-
enzyme.2 TNF-² (also known as lymphotoxin-Ä…) can be ecule (ICAM) 1, vascular cell adhesion molecule
synthesized and processed as a typical secretory protein (VCAM) 1, and E-selectin, thus permitting the egress of
but is usually linked to the cell surface by forming het- granulocytes into inflammatory loci. TNF is a potent
erotrimers with a third, membrane-associated, member activator of neutrophils, mediating adherence, chemo-
of this family, LT-². TNF-Ä… and TNF-² bind to the same taxis, degranulation, and the respiratory burst. Enthusi-
two distinct cell surface receptors TNFR I (p55) and asm for the potential therapeutic value of TNF to treat
TNFR II (p75) with similar affinities, and produce sim- malignancies has been tempered by its severe side
ilar although not identical effects.3 TNFs induce antitu- effects. TNF is responsible for the severe cachexia that
S462 Borish and Steinke J ALLERGY CLIN IMMUNOL
FEBRUARY 2003
TABLE I. Innate immune receptors
spectrum of changes associated with being ill. IL-1 inter-
Receptor Ligand acts with the central nervous system to produce fever,
lethargy, sleep, and anorexia. An IL-1 hepatocyte interac-
TLR2 Gram-negative bacterial LPS (endotoxin) through
tion inhibits production of  housekeeping proteins (eg,
CD14-dependent pathway
albumin) and stimulates the synthesis of acute phase
Mycobacterial glycolipids lipoarabinomannan
response peptides (eg, amyloid peptide, C-reactive pep-
(AraLAM) and mannosylated phosphatidylinositol
(PIM), Peptidoglyan (PGN) tide, complement). IL-1 stimulates endothelial cell adher-
TLR3 Double-stranded RNA (viral-derived RNA)
ence of leukocytes through the upregulation of ICAM-1,
TLR4 Gram-negative bacterial LPS (lipid A; endotoxin),
VCAM-1, and E-selectin. IL-1 contributes to the hypoten-
Heath shock protein 6
sion of septic shock. TNF and IL-1 share numerous bio-
Plant product Taxol
logical activities, the major distinction being that TNF has
RSV protein F
no direct effect on lymphocyte proliferation.
Lipoteichoic acid (LTA)
IL-1ra is secreted naturally in inflammatory processes.
TLR5 Flagellin, Salmonella, Microbial lipoproteins
Its production is upregulated by many cytokines, includ-
TLR6 Proteoglycans (bacterial) with TLR2
ing IL-4, IL-6, IL-13, and transforming growth factor ²
TLR9 CpG
(TGF-²). Production of IL-1ra is thought to modulate the
potentially deleterious effects of IL-1 in the natural
course of inflammation.
occurs in chronic infections and cancer.1 Furthermore,
Interleukin-6
TNF induces vascular leakage, has negative inotropic
effects, and is the primary endogenous mediator of toxic Mononuclear phagocytic cells are the most important
shock and sepsis.4 source of IL-69; however, IL-6 is also produced by T and
B lymphocytes, fibroblasts, endothelial cells, ker-
Interleukin-1
atinocytes, hepatocytes, and bone marrow cells. Under the
The IL-1 family represents four peptides (IL-1Ä…, IL- influence of IL-6, B lymphocytes differentiate into mature
1², the IL-1 receptor antagonist [IL-1ra], and IL-18).5 plasma cells and secrete immunoglobulins. IL-6 mediates
IL-1Ä… and IL-1² have similar biological activities, and T-cell activation, growth, and differentiation. In addition
both of these proteins along with IL-1ra interact with to lymphocyte activation, IL-6 shares several activities
similar affinities to the two IL-1 receptors (IL-1Rs). Type with IL-1, including the induction of pyrexia and the pro-
I receptors transduce the biological effects attributed to duction of acute phase proteins. IL-6 is considered the
IL-1.6 These are in contrast to type II receptors, which most important inducer of hepatocyte synthesis of acute-
are expressed on B cells, neutrophils, and bone marrow phase proteins. In contrast to these proinflammatory
cells and have a minimal intracellular domain. The  cap- effects, IL-6 mediates several anti-inflammatory effects.
ture and sequestration of IL-1 by these inactive type II Whereas both IL-1 and TNF induce synthesis of each
receptors serves an anti-inflammatory function and other, as well as IL-6, IL-6 terminates this upregulatory
hence are sometimes referred to as decoy receptors. The inflammatory cascade and inhibits IL-1 and TNF synthe-
capacity of IL-1ra to bind to the type I (proinflammato- sis. Furthermore, IL-6 stimulates synthesis of IL-1ra.
ry) IL-1R without transducing biological activities is the
Interleukins-12, -18, and -23
basis for its capacity to function as a cytokine antago-
nist.7 IL-1 is primarily produced by cells of the mono- IL-12 is derived from monocytes and macrophages but
nuclear phagocytic lineage but is also produced by also B cells, dendritic cells, Langerhans cells, polymor-
endothelial cells, keratinocytes, synovial cells, osteo- phonuclear neutrophils (PMNs), and mast cells.10 The
blasts, neutrophils, glial cells, and numerous other cells. biologically active form is a heterodimer. The larger sub-
IL-1 production may be stimulated by a variety of agents, unit (p40) is homologous to the soluble receptor for IL-
including endotoxin, other cytokines, microorganisms, 6, whereas the smaller subunit (p35) is homologous to
and antigens (Table I). Both IL-1Ä… and IL-1², as well as IL-6. Homodimers and monomers of the p40 peptide act
the related protein IL-18, are synthesized without a as competitive antagonists by binding to IL-12Rs without
secretory leader sequence as a less active precursor. The transducing activating signals. IL-12 activates and
mechanism for IL-1 and IL-18 secretion depends on their induces proliferation, cytotoxicity, and cytokine produc-
cleavage by a specific converting enzyme, termed IL-1 tion of NK cells. Other activities attributed to IL-12
converting enzyme (ICE) or caspase 1, which cleaves the include proliferation of T-helper and cytotoxic lympho-
procytokines into their active secreted forms.8 cytes. Its counterregulatory role in allergic inflammation
One of the most important biological activities of IL-1 is discussed later.
is its ability to activate T lymphocytes by enhancing the IL-18 was originally derived from the liver and is also
production of IL-2 and expression of IL-2 receptors. In produced by lung tissue, pancreas, kidney, and skeletal
the absence of IL-1, a diminished immune response or a muscle but not lymphocytes or NK cells.11 Similar to IL-
state of tolerance develops. IL-1 augments B-cell prolif- 1, IL-18 requires a specific converting enzyme (ICE or
eration and increases immunoglobulin synthesis. The pro- caspase-1) to permit secretion and activation. In contrast
duction of IL-1 during the immune response produces a to most cytokines, IL-18 is constitutively expressed, and
J ALLERGY CLIN IMMUNOL Borish and Steinke S463
VOLUME 111, NUMBER 2
release of its active form is regulated through activation Interferons
of this converting enzyme. However, its major biological
activity is more similar to that of IL-12 than IL-1. IL-18 There are three members of the IFN family (Ä…, ², and
has an important role in cellular adhesion, being the final Å‚), and their nomenclature is based on their ability to
common pathway used by IL-1 and TNF that leads to  interfere with viral growth. IFN-Ä… is primarily derived
ICAM-1 expression. IL-18 binds to a unique heterodimer from monocytes, macrophages, B lymphocytes, and NK
receptor. IL-18R expression is upregulated by IL-12, and cells. It has significant antiviral activity mediated
thereby these two cytokines synergize to stimulate inter- through its ability to inhibit viral replication within virus-
feron-Å‚ (IFN-Å‚) release. Soluble IL-18 receptors are infected cells, protect uninfected cells from infection,
derived from a unique gene that has lost its signaling and stimulate antiviral immunity by cytotoxic lympho-
domain and thereby functions as a natural decoy receptor cytes and NK cells. IFN-Ä… has other important biological
with potent anti-inflammatory functions.12 actions, including upregulation of class I MHC mole-
IL-23 is a recently described cytokine having homolo- cules and mediation of antitumor activity. IFN-² mirrors
gy to the p35 subunit of IL-12.13 It is a heterodimer con- many of the biological effects of IFN-Ä….
sisting of the unique IL-23Ä… chain and the p40 chain of IFN-Å‚ is primarily made by T cells and NK cells and to
IL-12. IL-23 is secreted by activated dendritic cells. As a lesser degree by macrophages. The biological activities of
with IL-12 and IL-18, it is a potent inducer of IFN-Å‚ and IFN-Å‚ include only modest antiviral activity and its deriva-
is presumed to contribute to TH1-like lymphocyte differ- tion primarily from T lymphocytes suggests that it may be
entiation. Its receptor includes the IL-12R²1 chain. more of an interleukin than an interferon. IFN-Å‚ and its
roles in cellular and allergic immunity are discussed later.
Interleukin-15
IL-15 has activity similar to that of IL-2 and is pri- HUMORAL IMMUNITY
marily distinguished from IL-2 through its use of a
unique Ä… chain as part of its receptor signaling com- At least two cytokines contribute to B-lymphocyte
plex.14 Both receptors share the use of the ² and Å‚ chain. maturation in the bone marrow, the lymphoid stem cell
Mononuclear phagocytic cells, epithelium, fibroblasts, growth factors IL-7 and IL-11. IL-7 is critically important
and placenta are other sources of IL-15, whereas activat- to the development of B and T lymphocytes through its
ed T lymphocytes, the most important source of IL-2, do production by stromal tissue of the bone marrow and thy-
not express IL-15. As discussed later, like IL-2, IL-15 is mus, from which it interacts with lymphoid precursors. In
a T-cell growth factor, is chemotactic for T lymphocytes, addition, IL-7 stimulates the proliferation and differentia-
differentiates NK cells, and stimulates B-cell growth and tion of cytotoxic T and NK cells and stimulates the tumo-
differentiation. IL-15 provides a mechanism by which ricidal activity of monocytes and macrophages.
mononuclear phagocytic cells can regulate T- and NK- After B cells egress from the bone marrow, isotype
cell proliferation and function in a fashion similar to T- switching, the activation of mature B cells into
cell derived IL-2. immunoglobulin-secreting B cells, and their final differ-
entiation into plasma cells are processes that are under T-
CYTOTOXIC IMMUNITY
cell control.16 Cytokines that trigger isotype switching
include IL-4 and IL-13, which induces the IgE isotype,
Immune responses directed against virus-infected and TGF-², which triggers IgA, and IL-10, which contributes
neoplastic cells are primarily mediated by CD8+ cytotox- to the generation of IgG4. Other cytokines that influence
ic lymphocytes and NK cells. Cytokines that activate B-cell maturation include IFN-Å‚, IL-1, IL-2, IL-5, IL-6,
cytotoxic immunity include IL-2, IL-4, IL-5, IL-6, IL-7, IL-12, IL-15, and IL-21.
IL-10, IL-12, and IL-15 which are discussed else-
CELLULAR IMMUNITY
where as well as IL-11 and, most importantly, TNF-Ä…,
TNF-², and the interferons. Interleukin-2
Interleukin-11
Stimulation of T cells by antigen in the presence
IL-11 was originally described as a stimulatory factor of accessory signals provided by the cytokines IL-1 and
for hematopoietic precursor cells. It contributes to lym- IL-6 and the cognate interaction of the B7 molecules
phoid production in the bone marrow and synergizes (CD80 or CD88) with CD28 induces the simultaneous
with other growth factors to produce erythrocytes, secretion of IL-2 and the expression of high-affinity
platelets, and mast cells. IL-11 stimulates the production IL-2R. Subsequently, the binding of secreted IL-2 to these
of acute phase proteins and induces lymphoid cell differ- IL-2R positive T cells induces clonal T-cell proliferation.
entiation. IL-11 is an important stimulatory factor for The requirement for both IL-2 production and IL-2R
connective tissue cells such as fibroblasts. A role for IL- expression for T-cell proliferation ensures that only T cells
11 in asthma remodeling is suggested by studies demon- specific for the antigen inciting the immune response
strating expression of IL-11 in severe asthma,15 and the become activated. In addition to its role as a T-cell growth
capacity of this cytokine to stimulate fibroblast prolifer- factor, IL-2 is also involved in activation of NK cells, B
ation and collagen deposition. cells, cytotoxic T cells, and macrophages.
S464 Borish and Steinke J ALLERGY CLIN IMMUNOL
FEBRUARY 2003
Interleukin-21 gen defines atopy. The regulation of IgE is primarily a func-
tion of the relative activities of IL-4, IL-13, and IFN-Å‚.
IL-21 is a newly described cytokine having homology Interleukin-4. In addition to T-helper lymphocytes, IL-
to both IL-2 and IL-15, which is predominantly produced 420 is derived from eosinophils, basophils, and possibly
by activated T lymphocytes.17 IL-21 receptors are mast cells. In both eosinophils and mast cells, IL-4 exists
expressed on activated B, T, and NK cells. It shares as a preformed, granule-associated peptide and can be
numerous biological activities with IL-2 and IL-15, rapidly released in allergic inflammatory responses. IL-4
including the capacity to activate NK cells and promote stimulates MHC class II molecules, B7, CD40, surface
the proliferation of B and T lymphocytes. IgM, and low-affinity IgE receptor (CD23) expression by
B cells, thereby enhancing the antigen-presenting capac-
Interferon-Å‚
ity of B cells. IL-4 induces the immunoglobulin isotype
The most important cytokine responsible for cell- switch from IgM to IgE.21,22 Other B-cell activat-
mediated immunity is IFN-Å‚.18 It is primarily produced by ing cytokines, such as IL-2, IL-5, IL-6, and IL-9, syner-
T-helper lymphocytes but is also derived from cytotoxic T gize with IL-4 to increase the secretion of IgE. IL-4 has
cells and NK cells. IFN-Å‚ mediates increased MHC class been identified in the serum, bronchoalveolar lavage
I and II molecule expression. IFN-Å‚ stimulates antigen fluid, and lung tissue of asthmatic subjects, in nasal
presentation and cytokine production by monocytes and polyp tissue, and in the nasal mucosa of subjects with
also stimulates monocyte effector functions, including allergic rhinitis.
adherence, phagocytosis, secretion, the respiratory burst, In addition to these effects on B cells, IL-4 has impor-
and nitric oxide production. The net result is the accumu- tant influences on T-lymphocyte growth, differentiation,
lation of macrophages at the site of cellular immune and survival, producing important influences on allergic
responses, with their activation into macrophages capable inflammation. As will be discussed later, IL-4 drives the
of killing intracellular pathogens. In addition to its effects initial differentiation of naïve T-helper type 0 (TH0) lym-
on mononuclear phagocytes, IFN-Å‚ stimulates killing by phocytes toward a TH2 phenotype. IL-4 is also important
NK cells and neutrophils. It stimulates adherence of gran- in maintaining allergic immune responses by preventing
ulocytes to endothelial cells through the induction of apoptosis of T lymphocytes.23 The production of IL-4 by
ICAM-1, an activity shared with IL-1 and TNF. As with TH2 lymphocytes renders these cells refractory to the
other interferons, IFN-Å‚ inhibits viral replication. As dis- anti-inflammatory influences of corticosteroids.
cussed later, IFN-Å‚ is an inhibitor of allergic responses Other activities of IL-4 include enhancing the expres-
through its capacity to inhibit IL-4 mediated effects. sion of MHC molecules and low-affinity IgE receptors
(CD23) on macrophages. In contrast to these proinflam-
Interleukins-16 and -17
matory effects on monocytes, IL-4 downregulates anti-
Additional cytokines that are secreted by T-helper lym- body-dependent cellular cytotoxicity (ADCC), inhibits
phocytes and contribute to cell-mediated immunity are expression of Fc receptors, inhibits their differentiation
TNF-², IL-16, and IL-17. IL-16 is a T-cell derived prod- into macrophages, and downregulates production of
uct that is chemotactic for CD4+ lymphocytes, nitric oxide, IL-1, IL-6, and TNF-Ä… while stimulating
eosinophils, and monocytes and uses the CD4 molecule production of IL-1ra. Another important activity of IL-4
as its receptor.19 Its production is upregulated by TNF-Ä…, in allergic inflammation is its ability to induce expression
TGF-², IL-4, IL-9, and IL-13, as well as by histamine. IL- of VCAM-1 on endothelial cells. This produces
17 represents a family of cytokines that are expressed by enhanced adhesiveness of endothelium for T cells,
activated T cells predominantly of the memory phenotype eosinophils, basophils, and monocytes but not neu-
(CD4+CD45RO+) and also by eosinophils. IL-17 activates trophils, as is characteristic of allergic reactions.24 IL-4
macrophages, fibroblasts, and stromal cells, including but not IL-13 receptors are present on mast cells, where
their expression of ICAM-1 and secretion of cytokines they function to stimulate IgE receptor expression. An
(IL-6, IL-8, IL-11, granulocyte colony stimulating factor additional important influence of IL-4 on allergic inflam-
[G-CSF]), prostaglandin E2, and nitric oxide. IL-17 mation is its ability to induce mast cell expression of the
expression is increased in asthma, in which its ability to enzyme leukotriene C4 (LTC4) synthase, thereby deter-
activate fibroblasts suggests a role in airway remodeling. mining the capacity of mast cells to produce cysteinyl
leukotrienes.25 IL-4 stimulates mucin production and
ALLERGIC IMMUNITY
contributes to the excessive mucous production in the
asthmatic airway. Functional IL-4 receptors are het-
A final possible outcome of T-cell activation is the erodimers consisting of the IL-4RÄ… chain interacting
development of allergic immunity. Several features with the shared Å‚ chain or the IL-13RÄ…1 chain.26 The
specifically associated with the asthmatic state are regu- shared use of the IL-4RÄ… chain by IL-13 and IL-4 and the
lated by cytokines. These include the regulation of IgE, activation by this chain of the signaling protein Stat6
eosinophilia, and mast cell proliferation. explains many of the common biological activities of
these two cytokines.
Regulation of IgE
Interleukin-13. IL-13 is homologous to IL-4 and
The inappropriate production of IgE in response to aller- shares much of its biological activities on mononuclear
J ALLERGY CLIN IMMUNOL Borish and Steinke S465
VOLUME 111, NUMBER 2
phagocytic cells, endothelial cells, epithelial cells, and B Interleukin-5. IL-5 is the most important eosino-
cells. Thus IL-13 induces the IgE isotype switch and philopoietin, and mice transgenic for constitutive IL-5
VCAM-1 expression.27 Functional IL-13 receptors are a expression have eosinophilia.32 In addition to stimulating
heterodimer containing the IL-4RÄ… chain and a unique eosinophil production, IL-5 is chemotactic for eosinophils
IL-13RÄ…1 chain. The two IL-13RÄ… chains that have been and activates mature eosinophils, inducing eosinophil
described include the active form of the receptor IL- secretion and enhanced cytotoxicity. Another mechanism
13RÄ…1 and a putative inhibitory receptor, IL-13RÄ…2, by which IL-5 promotes accumulation of eosinophils is
which lacks the motif required for the binding of Janus through its ability to upregulate responses to chemokines
kinases.28 IL-13RÄ…1 expression is more limited than IL- and Ä…d²2 integrins on eosinophils, thereby promoting
4 receptors and includes endothelial cells, B cells, their adherence to VCAM-1 expressing endothelial cells.
mononuclear phagocytes, and basophils but not mast IL-5 prolongs eosinophil survival by blocking apopto-
cells or T cells. This more limited distribution of IL- sis.33 Administration of IL-5 to human beings causes
13RÄ…1 explains the unique ability of IL-4 to induce TH2 mucosal eosinophilia and an increase in bronchial hyper-
lymphocyte differentiation and mast cell activation. reactivity. Other activities of IL-5 include maturation of
However, IL-13 is more widely produced than IL-4, cytotoxic T lymphocytes and basophilic differentiation. In
including by TH1-like lymphocytes and is more readily addition to T-helper lymphocytes, other sources for IL-5
identified in allergic inflammatory tissue.29 IL-13 over- include mast cells, natural T cells, and perhaps
expressing mice have eosinophilic inflammation, mucus eosinophils themselves. IL-5 interacts with specific IL-
hypersecretion, airway fibrosis, and nonspecific airway 5Rs that consist of a heterodimer containing IL-5RÄ… and
hyperreactivity (AHR). a ² chain (CD131) shared with GM-CSFR and IL-3R.34
Interleukin-9. IL-9 was originally described as a mast Interleukin-3 and GM-CSF. In addition to IL-5, two
cell growth factor30 and contributes to mast cell mediat- CSFs, IL-335 and GM-CSF,36 contribute to the activity of
ed allergic responses through its ability to stimulate the eosinophils in allergic inflammation through their capaci-
production of mast cell proteases and the IgE high-affin- ties to prolong eosinophil survival and to generate activat-
ity receptor Ä… chain. IL-9 supports the growth and sur- ed eosinophils. IL-3 is an important factor that supports
vival of antigen-specific T lymphocytes. IL-9 is derived the growth of precursors for a variety of hematopoietic
from eosinophils and TH2-like lymphocytes. Its selective cells, including dendritic cells, erythrocytes, granulocytes
production by TH2 cells suggests a role in allergic (especially basophils), macrophages, mast cells, and lym-
inflammation and, in human T lymphocytes, this is a fea- phoid cells. The major source of IL-3 is T lymphocytes,
ture shared only with IL-4, IL-5, and IL-25. IL-9 has but in allergic inflammation it is also derived from
other important activities in allergic inflammation eosinophils and mast cells.
including inducing expression of CCL11 (eotaxin), IL-5 Like IL-3, GM-CSF is an important CSF that primar-
receptors, and chemokine receptor 4. It synergizes with ily supports the maturation of dendritic cells, neutrophils,
IL-4 to enhance the production of IgE and with IL-5 to and macrophages. GM-CSF also synergizes with other
enhance the production of eosinophils. CSFs to support the production of platelets and erythro-
Interferon-Å‚. The third cytokine critically important in cytes. GM-CSF is an activating factor for mature neu-
the regulation of IgE synthesis is IFN-Å‚. IFN-Å‚ functions trophils and mononuclear phagocytic cells. The role of
as an inhibitor of allergic responses through its capacity GM-CSF in allergic immunity is derived from its shared
to inhibit IL-4 mediated expression of low-affinity IgE ability with IL-3 and IL-5 to inhibit apoptosis of
receptors and the isotype switch to IgE. The downregula- eosinophils and thereby prolong the survival of
tion of IL-4 and IL-13 dependent IgE production is eosinophils at sites of allergic inflammation. GM-CSF
therefore a product of IFN-Å‚, but physiologically this activates mature eosinophils, increasing their degranula-
results as a consequence of the biological activity of the tion, cytotoxicity, and response to chemoattractants. As
IFN-Å‚ inducers IL-12, IL-18, and IL-23. noted, all three of these eosinophil-activating
Interleukin-25. A recently described cytokine, IL-25 cytokines IL-5, IL-3, and GM-CSF bind to Ä…² het-
contributes to IgE secretion through its ability to stimulate erodimer receptors, which have unique Ä… chains but
IL-4 and IL-13 production.31 Similar to IL-4, IL-5, and share the common ² chain.
IL-9, it is derived from TH2-like lymphocytes. It stimu-
Mast cell proliferation and activation
lates release of IL-4, IL-5, and IL-13 from nonlymphoid
accessory cells. Intraperitoneal injection of mice with IL- Increased numbers of mast cells characterize allergic
25 leads to enhanced IL-4 and IL-13 production, which is diseases, and, as with elevated IgE concentrations and
associated with increased IgE production. IL-25 stimula- eosinophilia, this is a T-cell dependent process. The most
tion of IL-5 production promotes blood eosinophilia, and important cytokine responsible for mast cell growth and
mice treated with IL-25 have eosinophilic inflammation. proliferation is stem cell factor (SCF, or c-kit ligand).37
SCF is derived from bone marrow stromal cells, endothe-
Eosinophilia
lial cells, and fibroblasts. SCF induces histamine release
Another characteristic feature of allergic diseases is from human mast cells but not basophils and remains the
the presence of increased numbers of activated circulat- only cytokine with this property. The importance of this
ing eosinophils. factor in human beings is supported by clinical observa-
S466 Borish and Steinke J ALLERGY CLIN IMMUNOL
FEBRUARY 2003
tions that the local administration of SCF is associated cytes, mast cells, and mononuclear phagocytic cells. The
with mast cell histamine release38 and when administered primary T-cell source for IL-10 is the Tr1 lymphocyte.
systemically is associated with cutaneous mast cell pro- However, monocytes and B cells are the major sources of
liferation and chronic urticaria. In addition to being essen- IL-10 in human beings. IL-10 inhibits production of IFN-Å‚
tial for mast cell differentiation, SCF interacts with other and IL-2 by TH1 lymphocytes; IL-4 and IL-5 by TH2
hematopoietic growth factors to stimulate myeloid, lym- lymphocytes43; IL-1², IL-6, IL-8, IL-12, and TNF-Ä… by
phoid, and erythroid progenitor cells. Several cytokines, mononuclear phagocytes; and IFN-Å‚ and TNF-Ä… by NK
especially including IL-3, IL-5, IL-6, IL-9, IL-10, IL-11, cells. In addition, IL-10 inhibits monocyte MHC class II
and nerve growth factor, may also contribute to mast cell molecule, CD23, ICAM-1, and B7 expression. Inhibition
proliferation.39 In addition to the factors that stimulate of B7 expression results in the inhibition of the ability of
mast cell proliferation, several cytokines have been the APC to provide the accessory signal necessary for T-
demonstrated to induce histamine release from basophils. helper activation.44 This inhibition of accessory function
These histamine-releasing factors include several mem- is primarily responsible for the inhibition of TH1 and TH2
bers of the chemokine family. cytokine production. Constitutive expression of IL-10 by
APCs in the respiratory tract of normal subjects has a
ANTI-INFLAMMATORY CYTOKINES
critical role in the induction and maintenance of toler-
ance to allergens and otherwise benign bioaerosols. In
In addition to cytokines that stimulate cytotoxic, cel- contrast, asthma and allergic rhinitis are associated with
lular, humoral, and allergic inflammation, several diminished IL-10 expression in the allergic airway,
cytokines have predominantly anti-inflammatory effects which will contribute to the development of an inflam-
including, as previously discussed, IL-1ra but also TGF- matory milieu.45 Support for a modulating role for IL-10
² and members of the IL-10 family. in human allergic disease is further derived from obser-
vations that IL-10 inhibits eosinophil survival and IL-
Transforming growth factor ²
4 induced IgE synthesis. These inhibitory effects of IL-
TGF-² represents a family of peptides that regulate cell 10 are in contrast to its effect on B lymphocytes, in which
growth, having both stimulatory and inhibitory effects on it functions as an activating factor that stimulates cell
different cell types.40 It is produced primarily by chon- proliferation and Ig secretion. IL-10 enhances isotype
drocytes, osteocytes, fibroblasts, platelets, monocytes, switching to IgG4 and functions as a growth cofactor for
and some T cells. The TGF-² producing T-helper lym- cytotoxic T cells. Thus IL-10 inhibits cytokines associat-
phocyte has been proposed to represent a distinct pheno- ed with cellular immunity and allergic inflammation
type termed the T repressor (Tr1) or T-helper type 3 (TH3) while stimulating humoral and cytotoxic immune
cell. TGF-² is synthesized as an inactive precursor that responses. TNF-Ä… and other cytokines stimulate IL-10
requires proteolytic cleavage to become active. TGF-² is secretion, suggesting a homeostatic mechanism whereby
an important stimulant of fibrosis, inducing formation of an inflammatory stimulus induces TNF-Ä… secretion,
the extracellular matrix, and it promotes wound healing which in turn stimulates IL-10 secretion, which feeds
and scar formation. In immunity, it is inhibitory for B back to terminate TNF-Ä… synthesis.
lymphocytes and T-helper and cytotoxic lymphocytes. It IL-19 is a member of the IL-10 family, and its expres-
inhibits immunoglobulin secretion by B lymphocytes and sion by monocytes can be induced by LPS and GM-CSF.
cytotoxicity of mononuclear phagocytes and NK cells. In IL-20, another recently described member of the IL-10
general, it inhibits the proliferation of many different cell family, is predominantly expressed by keratinocytes in the
types. Production of TGF-² by apoptotic T cells creates skin and is overexpressed in psoriasis.46 An additional
an immunosuppressive milieu and is one explanation for new member of the IL-10 family IL-22 is derived from T
the absence of inflammation and autoimmunity as a con- lymphocytes and mast cells, and its expression is induced
sequence of apoptotic cell death.41 In contrast to these by IL-9 and LPS. The predominant biological activity
anti-inflammatory effects, TGF-² is a chemoattractant for described for IL-22 is induction of acute phase responses.
macrophages and supports the Ä… isotype switch to IgA by Finally, IL-24 is the fourth new member of the IL-10 fam-
B cells.42 Production of TGF-² in gut lymphoid tissue is ily and is produced by murine TH2 lymphocytes in an IL-
responsible for secretory IgA production and is critical for 4 inducible fashion. Similar to IL-19, IL-20, and IL-22, it
the maintenance of immune nonresponsiveness to other- does not inhibit cytokine production by mononuclear
wise benign gut pathogens and food allergens. TGF-² is cells, an activity that remains unique for IL-10.
also constitutively produced in the healthy lung. In aller-
gic inflammation, the expression of TGF-² may be asso- T-HELPER LYMPHOCYTE FAMILIES
ciated with the fibrosis observed in asthma. TGF-² may
lessen allergic inflammation through a capacity to inhibit Subclasses of T-helper lymphocytes can be identified
IgE synthesis and mast cell proliferation. on the basis of their repertoire of cytokines47 (Table II).
Naive TH0 lymphocytes produce primarily IL-2 but may
Interleukins-10, -19, -20, -22, and -24
also synthesize cytokines characteristic of both TH1 and
IL-10 is a product of numerous cells, including TH1 TH2 lymphocytes. In human beings, TH1 lymphocytes
and TH2 lymphocytes,43 cytotoxic T cells, B lympho- produce interferon-Å‚ and TNF-² but not IL-4 and IL-5.
J ALLERGY CLIN IMMUNOL Borish and Steinke S467
VOLUME 111, NUMBER 2
TABLE II. T-helper cell subtypes classified by cytokine
Type 2 helper lymphocytes produce IL-4, IL-5, IL-9, and
production
IL-25 but not IFN-Å‚ or TNF-². Both classes produce
GM-CSF, TNF-Ä…, IL-2, IL-3, IL-10, and IL-13. Although T-helper
lymphocyte family Cytokines
distinct TH1/TH2 cytokine profiles may not be apparent
in human cells, there remains an inverse relation between
TH0 IL-2
the tendency of T lymphocytes to produce IFN-Å‚ as
TH1 IFN-Å‚, TNF-²
opposed to IL-4 or IL-5. Type 1 helper lymphocytes acti- TNF-Ä…, GM-CSF, IL-2, IL-3, IL-10, IL-13
TH2 IL-4, IL-5, IL-9, IL-25
vate T cells and monocytes and promote cell-mediated
TNF-Ä…, GM-CSF, IL-2, IL-3, IL-10, IL-13
immune responses and are important in antibody-depen-
Tr1 (TH3) TGF-², IL-10
dent immunity. Type 2 T-helper lymphocytes produce IL-
4, IL-5, and IL-13 and function in the relative absence of
IFN-Å‚ to induce allergic immune responses. TH3 lym-
phocytes produce the immunosuppressive cytokines
TGF-² and IL-10 and may be important in actively sup-
pressing or terminating immune responses.48
One of the more important questions in understanding transducers and activators of transcription (STATs),
the cause of allergic disorders is to determine the basis which uniquely function in cytokine signaling.51,52
for TH1/TH2 lymphocyte differentiation in response to The role for JAK family members in the pathway to
allergen. One of the most critical elements in determin- gene activation was largely deduced from studies of sig-
ing T-helper differentiation is the cytokine milieu in nal transduction by the IFN receptors. The two chains of
which the T lymphocyte is activated. The major determi- the IFN-Ä… receptor bind JAK1 and TYK2, respectively,
nant of TH2 lymphocyte differentiation is the cytokine whereas the two chains of the IFN-Å‚ receptor bind JAK1
IL-4.49 The original source of the IL-4 responsible for and JAK2. The receptors and the JAKs themselves
TH2 lymphocyte differentiation is unclear but is likely to become phosphorylated, and this phosphorylated com-
be provided by the naïve TH0 lymphocytes themselves. plex becomes the catalyst for the phosphorylation of
Mast cells and natural T lymphocytes may also have a cytoplasmic substrates. There are four JAKs: JAK1,
role in occasional circumstances. The result, however, is JAK2, JAK3, and TYK2, and, as such, receptor signaling
that in a milieu in which allergic inflammation is present is mediated by a surprisingly limited number of highly
(eg, bronchial lymphatics), more and more extensive redundant tyrosine kinases. For example, JAK2 is
allergenic responses against bystander antigens are involved in GM-CSF, G-CSF, IL-6, and IL-3 signaling.
expected to develop. TH1 lymphocyte differentiation is JAK1 and JAK3 are tyrosine-phosphorylated in response
mediated by IL-12, IL-18, and IL-23.50 Insofar as to IL-2, IL-4, and all the other cytokines whose receptors
mononuclear phagocytes are the major source of IL-12, are members of the Å‚c family.
this suggests a mechanism whereby antigens more likely Once engagement of a cytokine receptor has led to
to be processed by macrophages, including bacterial anti- tyrosine phosphorylation of the receptor and of receptor-
gens and intracellular parasites, produce TH1 lymphocyte associated JAKs, the next step in signal transduction
responses. Like IL-12, IL-18 also induces the differenti- involves the tyrosine phosphorylation of the STATs.51,52
ation of TH1 lymphocytes, and IL-18 is a growth factor After their activation, these proteins migrate to the nucle-
for these cells. IL-23 is a heterodimer that uses one com- us, where they bind to specific regulatory sequences in
ponent of IL-12 and, similarly, uses the IL-12R²1 chain the promoters of cytokine-responsive genes, thereby ini-
for its receptor. It is a potent inducer of IFN-Å‚ and is tiating gene transcription (see Fig 2). As with the JAKs,
therefore likely to also contribute to TH1 lymphocyte dif- the function of STATs was originally characterized with
ferentiation. studies involving the biochemical events of IFN-induced
gene transcription. Ligand binding of IFN-Ä…/² induces
SIGNAL TRANSDUCTION BY CYTOKINE
the formation of a complex composed of three proteins:
RECEPTORS either Stat1Ä… (p91) or Stat1² (p84), Stat2 (p113), and a
non-STAT protein, p48. In contrast, the stimulation of
Cytokine receptors generally do not have cytoplasmic cells with IFN-Å‚ results in the tyrosine phosphorylation
domains with intrinsic tyrosine kinase activity; however, of Stat1 by JAK1 and JAK2 but not of Stat2. There are 4
cytokine receptors do activate cytoplasmic tyrosine kinas- additional members of the STAT family. Stat3, Stat4, and
es. These processes are displayed in Figure 2, with IL-4 Stat6 were identified as IL-6 , IL-12 , and IL-
and IL-12 used as models. The first step in the activation 4 inducible peptides, respectively. Although important in
of cytokine receptors is ligand-induced dimerization, cytokine signaling, Stat5 was originally defined as a pro-
which results in the juxtaposition of two contact surfaces, lactin-inducible peptide. Engagement of the IL-4 recep-
allowing their stable interaction with cytoplasm-derived tor leads to the activation of JAK1, which in turn phos-
tyrosine kinases. Although numerous biochemical cas- phorylates Stat6. Stat6 is necessary for IL-4 dependent
cades are involved in cytokine signaling, this discussion expression of IL-4RÄ…, µ heavy chain, MHC class II,
will primarily focus on two novel families of protein tyro- CD23, and mucin53 (Fig 2). An important endogenous
sine kinases, termed Janus kinases (JAKs), and the signal inhibitor of Stat6 is referred to as the suppressor of
S468 Borish and Steinke J ALLERGY CLIN IMMUNOL
FEBRUARY 2003
FIG 2. Model of intracellular signaling pathways leading to transcription modulation by IL-4 and IL-12. A
novel family of four related cytoplasmic protein tyrosine kinases, termed Janus kinases (JAKs), function in
cytokine signaling: JAK1, JAK2, JAK3, and TYK2. On binding of the ligand, the JAKs physically associate
with the receptor and mediate tyrosine kinase activity. JAK1 and JAK3 are activated in response to IL-4.
JAK1 binds to IL-4R, whereas JAK3 becomes physically linked to the shared Å‚c. Signaling mediated by IL-12
involves JAK2 and TYK2. Activation of the cytokine receptor leads to tyrosine phosphorylation of the recep-
tor and of receptor-associated JAKs. The next step in signal transduction involves tyrosine phosphorylation
of cytoplasmic factors termed signal transducers and activators of transcription (STATs). After activation,
these proteins become phosphorylated, form homodimers, and migrate to the nucleus, where they bind to
regulatory sequences in the promoters of cytokine-responsive genes. IL-4 signaling is mediated through
Stat6. Phosphorylation allows Stat6 to dimerize, and it then undergoes nuclear translocation. In the nucle-
us, Stat6 mediates the major biological activities of IL-4: µ germline and VCAM-1 transcription and TH2 dif-
ferentiation. Other signaling pathways, including the activation of the insulin receptor substrates 1 and  2,
mediate other biological activities including proliferation and inhibition of apoptosis. Homodimers of phos-
phorylated Stat4 mediate the biological activities of IL-12, including induction of IFN-Å‚ transcription and dif-
ferentiation of TH1 lymphocytes.
cytokine signaling 1 (SOCS-1).54 SOCS-1 inhibits IL- the cytokine receptor families. In this cascade, Ras, Raf-
4 induced activation of JAK1 and Stat6 and thereby 1, Map/Erk kinase kinase (MEKK), and mitogen-activat-
effectively inhibits IL-4 signaling. ed protein (MAP) kinases are sequentially phosphorylat-
Compared with the number of cytokines, relatively ed and activated. The MAP kinase pathway is associated
few STATs exist, so the signaling pathways of several with induction of several transcription factors such as c-
distinct cytokines share common STAT proteins. For myc, c-fos, and nuclear factor IL-6. This ras pathway is
example, epidermal growth factor (EGF), PGDF, M-CSF, activated by several growth factors as well as by the
IL-6, IL-11, and the interferons all activate Stat1Ä…. cytokines IL-2, IL-3, IL-5, and EPO. An example of
Mechanisms must exist that lead to the distinct respons- another distinct pathway used for cytokine signaling is
es to different cytokines. In part, these reflect the activi- provided by IL-4, which activates the signaling protein
ties of other signaling pathways stimulated by cytokine insulin response substrate 1 (IRS-1) and its homologue,
receptors. For example, the Ras-dependent pathway is IRS-2. IRS-1 and IRS-2 regulate cellular proliferation
also a major signaling pathway activated by members of and protection from apoptosis.
J ALLERGY CLIN IMMUNOL Borish and Steinke S469
VOLUME 111, NUMBER 2
CYTOKINES AND THE IMMUNE RESPONSES superfamily. This chapter will use the new systematic
nomenclature with the common names listed in paren-
TO ALLERGENS
theses the first time the chemokine is described.58 To
Bronchial biopsy specimens of patients with allergic date, 47 chemokines and 18 chemokine receptors have
asthma, skin test challenge sites from atopic patients, and been described, which are listed in Table III, along with
the nasal mucosa in allergic rhinitis are all characterized the known chromosomal location and physiological
by the presence of T-helper lymphocytes displaying a properties of each. Many of the chemokine receptors can
TH2-like cytokine profile. However, although there may bind more than one ligand, allowing extensive overlap
be a reduced presence of the TH1 cytokines, allergic and redundancy of chemokine function.
inflammatory tissue is also characterized by the presence Although chemotaxis stands as the hallmark feature of
of IFN-Å‚, and it is likely that IFN-Å‚ exacerbates allergic chemokines, their physiological role is more complex
inflammation through its ability to activate accessory cell than originally described, and new functions continue to
function, stimulate cytokine secretion, induce adhesion be identified. Originally, chemokines were described as
molecule expression, and activate eosinophils. The con- inflammatory, being produced at the site of infection or
cept that IFN-Å‚ promotes allergic inflammation is sup- in response to a proinflammatory stimulus. The inflam-
ported by data that IFN-Å‚ producing TH1 lymphocytes matory chemokines recruit and activate leukocytes to
exacerbate murine asthma.55 mount an immune response and initiate wound healing.
The pattern of cytokine response to allergens observed Other chemokines have now been shown to have a home-
in nonallergic individuals is even more complex. Normal ostatic or housekeeping function. These functions are
individuals are exposed to the same concentrations of involved in adaptive immune responses including lym-
allergens as their allergic counterparts living in the same phocyte trafficking, hematopoiesis, antigen sampling in
environment. Remaining healthy requires active systems secondary lymphoid tissue, and immune surveillance.59
that prevent the development of inflammation. It is fre- Homeostatic chemokines tend to be expressed in specif-
quently stated that the immune response to allergens in ic tissues or organs, whereas inflammatory chemokines
nonallergic subjects is characterized by TH1 lymphocyte can be produced by many cell types in multiple locations.
responses. However, functional TH1 lymphocyte
CLASSIFICATION OF CHEMOKINES
responses stimulate the recruitment and activation of
mononuclear phagocytes and are associated with cellular
immunity and granuloma formation, features not present As a group, the chemokines exhibit between 20% and
in healthy subjects. If present in vivo, these TH1 lympho- 50% homology and are characterized by the presence of
cytes must therefore be present in a milieu that prevents three to four conserved cysteine residues. They can be sub-
cellular inflammation from developing. The absence of divided into four families, based on the positioning of the
inflammation in normal subjects is maintained by influ- N-terminal cysteine residues (Table III). The C-X-C sub-
ences that promote the development of tolerance. family is characterized by the separation of the first two
Immune responses to allergens do develop in nonatopic cysteines by a variable amino acid. In the C-C subfamily,
subjects, but these responses are generally of a lower the cysteine residues are adjacent to each other. The major-
order of magnitude than those observed in allergic sub- ity of the known chemokines are contained in these two
jects. Thus, nonallergic subjects demonstrate decreased families. In addition, these groups may be distinguished by
allergen-induced T-cell proliferation and lower allergen- their primary target cell: the C-X-C subfamily primarily
specific IgG antibody responses compared with their targeting neutrophils and the C-C family targeting mono-
allergic counterparts.56 One influence contributing to cytes and T cells. A new family of chemokines has been
immune nonresponsiveness is diminished accessory cell identified that lack the first and third cysteine, containing
function. In contrast to asthmatic lungs, in the healthy a single cysteine residue in the conserved position, and are
lung, alveolar macrophages and dendritic cells have referred to as the  C subfamily. This subfamily includes
reduced or absent expression of B7, are unable to present the lymphocyte-specific chemotactic peptide XCL1 (lym-
allergen to T-helper lymphocytes, and cannot stimulate photactin). A fourth subfamily (CX3C) has been identified
cellular activation and proliferation.57 The cytokine in which the two N-terminal cysteine residues are separat-
milieu of the nonasthmatic respiratory tract is character- ed by three variable amino acids. To date, this family only
ized by elevated concentrations of IL-10 and TGF-², has one member, CX3CL1 (fractalkine), and it is unique in
which may also help mitigate inflammatory responses. that it is the only membrane-bound chemokine with a
mucin-like glycosylated stalk.
CHEMOKINES
RECEPTORS AND SIGNAL TRANSDUCTION
Chemokines are a group of small (8 to 12 kD) mole-
cules able to induce chemotaxis in a variety of cells Cell surface receptor number varies from 3000/cell for
including neutrophils, monocytes, lymphocytes, CCR1 and CCR2 on monocytes and lymphocytes to
eosinophils, fibroblasts, and keratinocytes. These mole- 40,000 to 50,000 per cell for CCR3 on eosinophils.
cules regulate activity through interactions with members A given cell can express multiple chemokine receptors;
of the 7-transmembrane, G-protein coupled receptor each of which can induce specific signals, suggesting
S470 Borish and Steinke J ALLERGY CLIN IMMUNOL
FEBRUARY 2003
TABLE III. CC, C, CXC, and CX3C chemokine/receptor families
Systematic name Chromosome Ligand Chemokine receptor(s) Physiological features
CC chemokine/receptor family
CCL1 17q11.2 I-309 CCR8 Inflamm
CCL2 17q11.2 MCP-1/MCAF CCR2 Inflamm
CCL3 17q11.2 MIP-1Ä…/LD78Ä… CCR1, CCR5 Inflamm
CCL4 17q11.2 MIP-1² CCR5 Inflamm
CCL5 17q11.2 RANTES CCR1, CCR3, CCR5 Inflamm
CCL6 Unknown Unknown Unknown Unknown
CCL7 17q11.2 MCP-3 CCR1, CCR2, CCR3 Inflamm
CCL8 17q11.2 MCP-2 CCR3 Inflamm
CCL9 Unknown Unknown Unknown Unknown
CCL10 Unknown Unknown Unknown Unknown
CCL11 17q11.2 Eotaxin CCR3 Inflamm
CCL12 Unknown Unknown CCR2 Unknown
CCL13 17q11.2 MCP-4 CCR2, CCR3 Inflamm
CCL14 17q11.2 HCC-1 CCR1 Unknown
CCL15 17q11.2 HCC-2/Lkn-1 CCR1, CCR3 Unknown
CCL16 17q11.2 HCC-4/LEC CCR1 Unknown
CCL17 16q13 TARC CCR4 Inflamm, Homeo
CCL18 17q11.2 DC-CK1/PARC Unknown Homeo
CCL19 9p13 MIP-3²/ELC CCR7 Homeo
CCL20 2q33-q37 MIP-3Ä…/LARC CCR6 Inflamm, Homeo
CCL21 9p13 6Ckine.SLC CCR7 Homeo
CCL22 16q13 MDC/STCP-1 CCR4 Inflamm, Homeo
CCL23 17q11.2 MPIF-1 CCR1 Unknown
CCL24 7q11.23 MPIF-2/Eotaxin-2 CCR3 Inflamm
CCL25 19p13.2 TECK CCR9 Homeo
CCL26 7q11.23 Eotaxin-3 CCR3 Inflamm
CCL27 9p13 CTACK/ILC CCR10 Homeo
CCL28 5(?) MEC CCR10 Inflamm, Homeo
C chemokine/receptor family
XCL1 1q23 Lymphotactin XCR1 Unknown
XCL2 1q23 SCM1-Ä… XCR1 Unknown
CXC chemokine/receptor family
CXCL1 4q12-q13 GROÄ…/MGSA-Ä… CXCR2 > CXCR1 Inflamm
CXCL2 4q12-q13 GRO²/MGSA-² CXCR2 Inflamm
CXCL3 4q12-q13 GROÅ‚/MGSA-Å‚ CXCR2 Inflamm
CXCL4 4q12-q13 PF4 Unknown Unknown
CXCL5 4q12-q13 ENA-78 CXCR2 Unknown
CXCL6 4q12-q13 GCP-2 CXCR1, CXCR2 Unknown
CXCL7 4q12-q13 NAP-2 CXCR2 Unknown
CXCL8 4q12-q13 IL-8 CXCR1, CXCR2 Inflamm
CXCL9 4q21.21 Mig CXCR3 Inflamm
CXCL10 4q21.21 IP-10 CXCR3 Inflamm
CXCL11 4q21.21 I-TAC CXCR3 Inflamm
CXCL12 10q11.1 SDF-1Ä…/² CXCR4 Unknown
CXCL13 4q21 BLC/BCA-1 CXCR5 Homeo
CXCL14 5q31 BRAK/bolekine Unknown Homeo
CXCL15 Unknown Unknown Unknown Unknown
CXCL16 17p13 Unknown CXCR6 Inflamm
CX3C chemokine/receptor family
CX3CL1 16q13 Fractalkine CX3CR1 Inflamm
This table is an adaptation of the tables presented by Zlotnik et al54 and Moser et al.55 The terms Inflamm and Homeo under the physiological features heading
refer to inflammatory chemokines and homeostatic chemokines, respectively. The most common names for the human ligands are listed, but is not all inclusive
of ligand names found in the literature.
that each receptor signals through different pathways. with the Ä… and ²Å‚ subunits of the heterotrimeric G pro-
The ability to signal through different pathways is due in teins and other effector molecules, is created by looping
part to the heptahelical transmembrane property of the of the receptor along the inner plasma membrane and the
receptors. A large surface area, allowing interactions lateral orientation of the carboxy terminus.60
J ALLERGY CLIN IMMUNOL Borish and Steinke S471
VOLUME 111, NUMBER 2
Signaling is initiated after binding of the chemokine to leukotriene B4 (LTB4) appears within minutes of cellular
the receptor, which allows the association of guanine activation and its concentration peaks at 3 hours. As LTB4
triphosphate (GTP) to the GÄ… subunit. This results in dis- concentrations decline, the newly synthesized CXCL8
sociation of the heterotrimeric G-protein complex from begins to be secreted and persists for at least 24 hours.
the receptor and separation into the GÄ… and G²Å‚ subunits. Other members of the chemokine family, including CCL3
The GÄ… subunit is able to directly activate the Src family (MIP-1Ä…), share this capacity to activate PMNs.
kinases, which then leads to activation of the mitogen- Chemokines perform a variety of functions aside from
activated protein kinases (MAPKs) and protein kinase B chemotaxis. Chemokines can have direct effects on T-
(PKB).9 Signaling through the G²Å‚ subunit is more com- cell differentiation through ligand-receptor interactions
plex and involves at least three separate pathways. G²Å‚ on the developing cell or indirectly by altering APC traf-
can activate PKB and the MAPKs through phosphatidyli- ficking or cytokine secretion. Functioning through the
nositol 3 kinase Å‚ (PI3KÅ‚), PKC through phospholipase C CCR5 receptor, CCL3 (MIP-1Ä…), CCL4 (MIP-1²), and
(PLC) and Pyk-2.61 Activation of PLC induces calcium CCL5 (RANTES) can directly promote development of
influx, which activates many cellular processes, including IFN-Å‚ producing TH1 lymphocytes or indirectly by
degranulation of neutrophils, eosinophils, and basophils increasing IL-12 production from APCs. In contrast,
(extensively reviewed by Thelen60). CCL2 (MCP-1), CCL7 (MCP-3), CCL8 (MCP-2), and
CCL13 (MCP-4) can inhibit IL-12 production from
LOCOMOTION
APCs and enhance IL-4 production from activated T
cells, leading to a TH2 lymphocyte phenotype.65
Chemokines were originally described as having a pri- Chemokine receptor expression can serve as a marker for
mary role in directing lymphocytes to sites of inflamma- maturation and differentiation of lymphocytes. When
tion. In a process mediated by the selectins, lymphocytes monocytes and immature dendritic cells migrate from the
interact transiently with the vascular endothelium while vasculature into tissues and begin immune surveillance,
searching for activating signals from chemokines. The they express the inflammatory receptors CCR1, CCR2,
selectins mediate low-affinity interactions, which, in CCR5, CCR6, and CXCR2. As antigen is encountered
combination with the shearing stress of blood flow, pro- and the dendritic cells mature, the inflammatory recep-
duce the process of  rolling adhesion. Upon binding of tors are downregulated and replaced by expression of
the chemokine to its receptor on the lymphocyte, inte- CCR7, which allows the dendritic cells to accumulate in
grins are upregulated and firmly adhere the leukocyte to the draining lymphatics and T-cell areas of the lymph
the vessel wall. An example of this has been demonstrat- nodes. CXCR5 is expressed on a distinct memory T-cell
ed for the chemokines CCL19 (ELC), CCL21 (SLC), and subset that displays B-helper cell function. These cells
CXCL12 (SDF-1), which can rapidly induce a high- respond to CXCL13 (BLC) and are directed to the B-cell
affinity state for the ²2-integrin LFA-1.62 Once the cell follicle to support production of antibodies.66
has ceased rolling, it will traverse the endothelium. A
CLINICAL RELEVANCE OF CHEMOKINES
protrusion known as a lamellipod is formed, which is
composed of a dense array of actin fibers. Movement of
the body of the cell results from contraction of myosin, This section will focus on the role of chemokines in
which pulls actin filaments from around the cell body. allergic disorders. The role of chemokines in neoplasia
The end result is movement of the main cell body toward has been covered in recent reviews,67,68 and the role of
the lamellipod.63 As the cell moves forward, the affinity chemokines in HIV infection and development of AIDS
of the adhesion molecules at the rear of the cell decreas- will be covered in Chapter 13. Increased levels of the
es. The lymphocyte will continue this process as it chemokines CCL2 (MCP-1), CCL3, CCL5 (RANTES),
migrates along a concentration gradient until it reaches CCL7 (MCP-3), CCL11 (eotaxin-1), CCL13 (MCP-4),
the source of the chemokine. The expression of specific CCL24 (eotaxin-2), and CXCL8 (IL-8) and CXCL10
chemokines, receptors, and adhesion molecules con- (IP-10) have been demonstrated in bronchoalveolar
tributes to the selective migration and tissue specificity of lavage and biopsy samples of asthmatic patients com-
lymphocytes. pared with control patients.69 In murine models of asth-
The most important chemoattractant for PMNs, ma, CCL2, CCL5, CCL11, and CXCL10 and CXCL12
CXCL8 (IL-8), is derived primarily from mononuclear (SDF-1) contribute to AHR and cellular emigration in a
phagocytes, endothelial, and epithelial cells but also from nonredundant fashion.
T cells, eosinophils, neutrophils, fibroblasts, ker- Because of their ability to recruit eosinophils, T cells,
atinocytes, and hepatocytes. CXCL8 synthesis may be and monocytes to regions of inflammation, the C-C
induced by lipopolysaccharide, IL-1, TNF, and viruses.64 chemokine family has been extensively studied in allergic
On a molar basis, CXCL8 is one of the most potent diseases. Unlike other eosinophil chemoattractants such
chemoattractants for neutrophils. It also stimulates neu- as LTB4, platelet-activating factor, and C5a, these
trophil degranulation, the respiratory burst, and adherence chemokines are more selective for eosinophils. CCL5
to endothelial cells by CD11b/CD18. During the inflam- (RANTES) and CCL11 (eotaxin) acting in synergy with
matory response, CXCL8 appears relatively late in com- IL-5 are the most important eosinophil chemoattractants
parison with other chemoattractants. For example, in allergic inflammation.70 Injection with CCL5 or
S472 Borish and Steinke J ALLERGY CLIN IMMUNOL
FEBRUARY 2003
TABLE IV. Cytokines and chemokines in allergy and asthma
Cytokine/chemokine Activity
IgE regulation IL-4, IL-13 µ Isotype switch
IL-25 Enhanced production of IL-4 and IL-13
IL-9 Synergizes with IL-4 and IL-13
IFN-Å‚, TGF-² Inhibition of IL-4 and IL-13
IL-4 Generation of IL-4 producing (TH2-like) T lymphocytes
CCL3, CCL4, CCL5 Recruitment of TH1-like cells
IL-12, IL-18, IL-23 Stimulation of IFN-Å‚ producing (TH1-like) T lympho-
cytes
CCL2, CCL7, CCL8, CCL13, CCL8, CCL13 Recruitment of TH2-like cells
IgA regulation TGF-²Ä… Isotype switch
Eosinophilia IL-5 Eosinophilopoietin
IL-25 Enhanced production of IL-5
IL-5, IL-3, GM-CSF, IL-4, TNF-Ä…, IFN-Å‚ Inhibition of apoptosis
IL-5, IL-3, GM-CSF, CCL3, CCL5, CCL7, Eosinophil chemotaxis, degranulation, and activation
CCL11, IL-1, TNF-Ä…, IFN-Å‚
Basophil activation CCL2, CCL3, CCL5, CCL7 Basophil chemotaxis and histamine release
Mast cell development Stem cell factor Mast cell growth and differentiation
IL-3, IL-4, IL-9, IL-10, IL-11, nerve growth Cofactors for mast cell growth
factor
Stem cell factor Mast cell histamine release
Adhesion molecule expression IL-1, IL-4, IL-13, TNF-Ä… Induction of VCAM-1
IL-1, TNF-Ä…, IFN-Å‚ Induction of ICAM-1
IL-1, TNF-Ä… Induction of E-Selectin
CCL19, CCL21, CXCL12 Upregulation of LFA-1
Airway hyperresponsiveness IL-4, IL-5, IL-9, IL-13, CCL2, CCL5,
CXCL10
Airway fibrosis and remodeling IL-4, IL-6, IL-9, IL-11, IL-13, IL-17, Promote fibroblast proliferation and collagen deposi-
TGF-Ä…, TGF-², PDGF, ²-FGF tion; subepithelial fibrosis
IL-4, IL-9, IL-13 Smooth muscle hyperplasia
CCL11 results in an eosinophilic and mononuclear infil- (MCP-3) from CCR1. Other properties include the abili-
trate in the absence of neutrophils. Aside from its produc- ty to inhibit Ca2+ mobilization, CD11b expression, and
tion by eosinophils, macrophages, mast cells, and T cells, leukocyte migration. In animal trials, BK471 was able to
CCL11 production has been described in structural cells reduce inflammation in allergic encephalomyelitis.72
of the airway including airway smooth muscle and fibrob- Instillation of CCL2 (MCP-1) in the lungs of mice
lasts. CCL17 (TARC) is expressed by nasal epithelial induced prolonged AHR associated with mast cell
cells, and that expression is higher in patients with aller- degranulation. Neutralization of CCL2 blocked the
gic rhinitis compared with control patients. IL-4 and IL- development of AHR in response to antigen. Several
13 stimulate CCL17 expression, thereby promoting a TH2 potential antagonists to CCL2 or its receptor CCR2 are
response.71 It is tempting to speculate that CCL17 expres- currently being developed. One of these is an indolop-
sion in the asthmatic lung could help drive TH2 respons- iperidine derivative that is able to selectively inhibit
es. CCL13 (MCP-4) may contribute to the allergic CCR2 without inhibiting the closely related CCR5 recep-
response by inducing histamine release from IL-3 primed tor.73 Thiazolidinedione (TZD) is a compound currently
basophils. These studies suggest that the priming of the being used to improve the insulin resistance of individu-
lung for an inflammatory response may be beneficial in als with diabetes mellitus. Studies using human lung
the clearance of viral or bacterial infections, but this is epithelial cell lines have demonstrated that TZD inhibit-
detrimental when dealing with nonspecific stimuli, as ed the IL-1² and TNF-Ä… induced expression of CCL2.
observed in the allergic response. In addition, the CCL2-induced chemotaxis of monocytes
was inhibited by TZD.74 Many of the chemokines that
CHEMOKINE ANTAGONISTS AS A
have been implicated in the asthmatic response, includ-
THERAPEUTIC OPTION ing CCL5, CCL11 (eotaxin), CCL13 (MCP-4), CCL24
(eotaxin-2), and CCL26 (eotaxin-3), function through the
Several compounds have been developed that antago- CCR3 receptor. Through the use of a mouse model, a
nize chemokine receptor function, some of which are neutralizing antibody to CCL11 reduced eosinophil
currently undergoing clinical trials. A nonpeptide CCR1 recruitment into the lung after allergen challenge and
antagonist has been identified (BX471) that is able to dis- reduced associated AHR. Both a nonpeptide antagonist
place CCL3 (MIP-1Ä…), CCL5 (RANTES), and CCL7 of CCR3, the CCL11 receptor (SB-328437), and an
J ALLERGY CLIN IMMUNOL Borish and Steinke S473
VOLUME 111, NUMBER 2
amino piperidine derivative of CCL11 (UCB-35625) also basophils, and lymphocytes. Many cytokines and
block eosinophil recruitment in allergen models of asth- chemokines may then contribute to the activation of these
ma and are currently undergoing clinical trials.75 Anoth- leukocytes once they reach the airways. Cytokines impor-
er compound that may prove beneficial is the CCR3 tant in promoting fibrosis and airway remodeling are IL-4,
receptor antagonist F-1322. F-1322 also inhibits throm- IL-6, IL-11, IL-13, IL-17, and TGF-².
boxane A2 synthase and 5-lipoxygenase and is a hista-
mine antagonist. In vitro, F-1322 inhibited CCL11-
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