Cytokines and chemokines.pdf

2. Cytokines and chemokines

Larry C. Borish, MD, and John W. Steinke, PhD Charlottesville, Va

Cytokines and chemokines are redundant secreted proteins

with growth, differentiation, and activation functions that reg-

ulate and determine the nature of immune responses and con-

trol immune cell trafficking and the cellular arrangement of

immune organs. Which cytokines are produced in response to

an immune insult determines initially whether an immune

response develops and subsequently whether that response is

cytotoxic, humoral, cell-mediated, or allergic. A cascade of

responses can be seen in response to cytokines, and often sev-

eral cytokines are required to synergize to express optimal

function. An additional confounding variable in dissecting

cytokine function is that each cytokine may have a completely

different function, depending on the cellular source, target,

and, most important, specific phase of the immune response

during which it is presented. Numerous cytokines have both

proinflammatory and anti-inflammatory potential; which

activity is observed depends on the immune cells present and

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-

sive. The biology of chemokines are then reviewed, grouped by

family. (J Allergy Clin Immunol 2003;111:S460-75.)

Abbreviations used

ADCC: Antibody-dependent cellular cytotoxicity

AHR: Airway hyperreactivity

APC: Antigen-presenting cells

GCSF: Granulocyte-colony stimulating factor

ICAM: Intercellular adhesion molecule

ICE: Interleukin-1 converting enzyme

IFN: Interferon

IL: Interleukin

LPS: Lipopolysaccharide

MAPK: Mitogen-activated protein kinase

NK: Natural killer

SCF: Stem cell factor

TGF-

particularly effective in promoting the cellular infiltrate

and damage to resident tissue characteristic of inflamma-

tion. The processing of antigens as they are taken up by

APCs, processed, and presented to T-helper lymphocytes

provides one pathway for this class of cytokine produc-

tion. Alternatively, monocytes are potently triggered to

produce cytokines through the innate immune system,

using pattern recognition receptors that recognize stereo-

typic components of pathogens that do not occur on

mammalian cells. These receptors, such as the

lipopolysaccharide (LPS) receptor, contribute to the abil-

ity of the immune system to distinguish pathogens from

nonpathogenic proteins to which the immune system may

become exposed. The cytokines predominantly produced

by monocytes include tumor necrosis factor (TNF), and

several interleukin (IL) molecules known as IL-1, IL-6,

IL-8, IL-12, IL-15, IL-18, and IL-23. IL-8 is also classi-

fied as a chemokine known as CXCL8; it and other

chemokines are also secreted by APCs.

Key words: Allergy, colony-stimulating factors, cytokines,

chemokines, chemotaxis, IgE, mast cells, mononuclear phago-

cytes, T lymphocytes

Cytokines are involved in virtually every facet of

immunity and inflammation, including innate immunity,

antigen presentation, bone marrow differentiation, cellu-

lar recruitment and activation, and adhesion molecule

expression (Fig 1). Which cytokines are produced in

response to an immune insult determines initially

whether an immune response develops and subsequently

whether that response is cytotoxic, humoral, cell-mediat-

ed, or allergic. For presentation in this review, cytokines

are grouped according to those that are predominantly

mononuclear phagocytic–derived or T-lymphocyte–

derived; those that predominantly mediate cytotoxic

(antiviral and anticancer), humoral, cell-mediated, or

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-

) and

Cytokines primarily derived from mononuclear phago-

cytic cells and other antigen-presenting cells (APCs) are

). 1 The active form of both

cytokines is a homotrimer. In addition to mononuclear

phagocytes, TNF-

may be produced by neutrophils,

activated lymphocytes, natural killer (NK) cells,

endothelial cells, and mast cells. The most potent induc-

er of TNF by monocytes is LPS, acting through toll-like

receptor 2 (TLR2) and TLR4. The toll-like receptors

(Table I) represent a family of pattern recognition recep-

tors that recognize motifs used by pathogens but not

mammalian cells and are capable of potently activating

From the University of Virginia Health System, Beirne Carter Center for

Immunology, Asthma and Allergic Disease Center, Charlottesville, Va.

Reprint requests: John W. Steinke, PhD, University of Virginia Health Sys-

tem, Beirne Carter Center for Immunology, Asthma and Allergic Disease

Center, Charlottesville, VA 22908-1355.

0091-6749/2003 $30.00 +0

doi:10.1067/mai.2003.108

S460

:Transforming growth factor–beta

TNF: Tumor necrosis factor

Tr:T repressor

VCAM: Vascular cell adhesion molecule

lymphocytes (TNF-

J ALLERGY CLIN IMMUNOL

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Borish and Steinke S461

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. T H 1-like lymphocytes are characterized by their production of IFN-

is processed as a

membrane-bound protein from which the soluble active

factor is derived by cleavage using the TNF-

mor immunity through direct cytotoxic effects on can-

cerous cells and by stimulating antitumor immune

responses. TNF interacts with endothelial cells to induce

adhesion molecules known as intracellular adhesion mol-

ecule (ICAM)–1, vascular cell adhesion molecule

(VCAM)–1, and E-selectin, thus permitting the egress of

granulocytes into inflammatory loci. TNF is a potent

activator of neutrophils, mediating adherence, chemo-

taxis, degranulation, and the respiratory burst. Enthusi-

asm for the potential therapeutic value of TNF to treat

malignancies has been tempered by its severe side

effects. TNF is responsible for the severe cachexia that

converting

) can be

synthesized and processed as a typical secretory protein

but is usually linked to the cell surface by forming het-

erotrimers with a third, membrane-associated, member

of this family, LT-

(also known as lymphotoxin-

bind to the same

two distinct cell surface receptors—TNFR I (p55) and

TNFR II (p75)—with similar affinities, and produce sim-

ilar although not identical effects. 3

. TNF-

and TNF-

TNFs induce antitu-

and primarily contribute to cellular

immunity. T H 2-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. T H 3-like lymphocytes have immunosuppressive tendencies and

are characterized by their production of IL-10 and TGF-

innate immune responses, including mononuclear phago-

cytic cell cytokine production. TNF-

enzyme. 2 TNF-

S462 Borish and Steinke

J ALLERGY CLIN IMMUNOL

FEBRUARY 2003

TABLE I. Innate immune receptors

Receptor Ligand

TLR2

Gram-negative bacterial LPS (endotoxin) through

CD14-dependent pathway

Mycobacterial glycolipids lipoarabinomannan

(AraLAM) and mannosylated phosphatidylinositol

(PIM), Peptidoglyan (PGN)

spectrum of changes associated with being ill. IL-1 inter-

acts with the central nervous system to produce fever,

lethargy, sleep, and anorexia. An IL-1–hepatocyte interac-

tion inhibits production of “housekeeping” proteins (eg,

albumin) and stimulates the synthesis of acute phase

response peptides (eg, amyloid peptide, C-reactive pep-

tide, complement). IL-1 stimulates endothelial cell adher-

ence of leukocytes through the upregulation of ICAM-1,

VCAM-1, and E-selectin. IL-1 contributes to the hypoten-

sion of septic shock. TNF and IL-1 share numerous bio-

logical activities, the major distinction being that TNF has

no direct effect on lymphocyte proliferation.

IL-1ra is secreted naturally in inflammatory processes.

Its production is upregulated by many cytokines, includ-

ing IL-4, IL-6, IL-13, and transforming growth factor–

TLR3

Double-stranded RNA (viral-derived RNA)

TLR4

Gram-negative bacterial LPS (lipid A; endotoxin),

Heath shock protein 6

Plant product Taxol

RSV protein F

Lipoteichoic acid (LTA)

TLR5

Flagellin, Salmonella, Microbial lipoproteins

TLR6

Proteoglycans (bacterial) with TLR2

TLR9

CpG

). 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,

TNF induces vascular leakage, has negative inotropic

effects, and is the primary endogenous mediator of toxic

shock and sepsis. 4

Interleukin-6

Mononuclear phagocytic cells are the most important

source of IL-6 9 ; however, IL-6 is also produced by T and

B lymphocytes, fibroblasts, endothelial cells, ker-

atinocytes, hepatocytes, and bone marrow cells. Under the

influence of IL-6, B lymphocytes differentiate into mature

plasma cells and secrete immunoglobulins. IL-6 mediates

T-cell activation, growth, and differentiation. In addition

to lymphocyte activation, IL-6 shares several activities

with IL-1, including the induction of pyrexia and the pro-

duction of acute phase proteins. IL-6 is considered the

most important inducer of hepatocyte synthesis of acute-

phase proteins. In contrast to these proinflammatory

effects, IL-6 mediates several anti-inflammatory effects.

Whereas both IL-1 and TNF induce synthesis of each

other, as well as IL-6, IL-6 terminates this upregulatory

inflammatory cascade and inhibits IL-1 and TNF synthe-

sis. Furthermore, IL-6 stimulates synthesis of IL-1ra.

Interleukin-1

The IL-1 family represents four peptides (IL-1

, IL-

, the IL-1 receptor antagonist [IL-1ra], and IL-18). 5

IL-1

have similar biological activities, and

both of these proteins along with IL-1ra interact with

similar affinities to the two IL-1 receptors (IL-1Rs). Type

I receptors transduce the biological effects attributed to

IL-1. 6 These are in contrast to type II receptors, which

are expressed on B cells, neutrophils, and bone marrow

cells and have a minimal intracellular domain. The “cap-

ture” and sequestration of IL-1 by these inactive type II

receptors serves an anti-inflammatory function and

hence are sometimes referred to as decoy receptors. The

capacity of IL-1ra to bind to the type I (proinflammato-

ry) IL-1R without transducing biological activities is the

basis for its capacity to function as a cytokine antago-

nist. 7 IL-1 is primarily produced by cells of the mono-

nuclear phagocytic lineage but is also produced by

endothelial cells, keratinocytes, synovial cells, osteo-

blasts, neutrophils, glial cells, and numerous other cells.

IL-1 production may be stimulated by a variety of agents,

including endotoxin, other cytokines, microorganisms,

and antigens (Table I). Both IL-1

and IL-1

as well as

the related protein IL-18, are synthesized without a

secretory leader sequence as a less active precursor. The

mechanism for IL-1 and IL-18 secretion depends on their

cleavage by a specific converting enzyme, termed IL-1

converting enzyme (ICE) or caspase 1, which cleaves the

procytokines into their active secreted forms. 8

One of the most important biological activities of IL-1

is its ability to activate T lymphocytes by enhancing the

production of IL-2 and expression of IL-2 receptors. In

the absence of IL-1, a diminished immune response or a

state of tolerance develops. IL-1 augments B-cell prolif-

eration and increases immunoglobulin synthesis. The pro-

duction of IL-1 during the immune response produces a

and IL-1

β,

Interleukins-12, -18, and -23

IL-12 is derived from monocytes and macrophages but

also B cells, dendritic cells, Langerhans cells, polymor-

phonuclear neutrophils (PMNs), and mast cells. 10 The

biologically active form is a heterodimer. The larger sub-

unit (p40) is homologous to the soluble receptor for IL-

6, whereas the smaller subunit (p35) is homologous to

IL-6. Homodimers and monomers of the p40 peptide act

as competitive antagonists by binding to IL-12Rs without

transducing activating signals. IL-12 activates and

induces proliferation, cytotoxicity, and cytokine produc-

tion of NK cells. Other activities attributed to IL-12

include proliferation of T-helper and cytotoxic lympho-

cytes. Its counterregulatory role in allergic inflammation

is discussed later.

IL-18 was originally derived from the liver and is also

produced by lung tissue, pancreas, kidney, and skeletal

muscle but not lymphocytes or NK cells. 11 Similar to IL-

1, IL-18 requires a specific converting enzyme (ICE or

caspase-1) to permit secretion and activation. In contrast

to most cytokines, IL-18 is constitutively expressed, and

(TGF-

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VOLUME 111, NUMBER 2

Borish and Steinke S463

release of its active form is regulated through activation

of this converting enzyme. However, its major biological

activity is more similar to that of IL-12 than IL-1. IL-18

has an important role in cellular adhesion, being the final

common pathway used by IL-1 and TNF that leads to

ICAM-1 expression. IL-18 binds to a unique heterodimer

receptor. IL-18R expression is upregulated by IL-12, and

thereby these two cytokines synergize to stimulate inter-

feron-

Interferons

There are three members of the IFN family (

, and

), and their nomenclature is based on their ability to

“interfere” with viral growth. IFN-

is primarily derived

from monocytes, macrophages, B lymphocytes, and NK

cells. It has significant antiviral activity mediated

through its ability to inhibit viral replication within virus-

infected cells, protect uninfected cells from infection,

and stimulate antiviral immunity by cytotoxic lympho-

cytes and NK cells. IFN-

release. Soluble IL-18 receptors are

derived from a unique gene that has lost its signaling

domain and thereby functions as a natural decoy receptor

with potent anti-inflammatory functions. 12

IL-23 is a recently described cytokine having homolo-

gy to the p35 subunit of IL-12. 13 It is a heterodimer con-

sisting of the unique IL-23

(IFN-

γ)

has other important biological

actions, including upregulation of class I MHC mole-

cules and mediation of antitumor activity. IFN-

mirrors

many of the biological effects of IFN-

chain and the p40 chain of

IL-12. IL-23 is secreted by activated dendritic cells. As

with IL-12 and IL-18, it is a potent inducer of IFN-

is primarily made by T cells and NK cells and to

a lesser degree by macrophages. The biological activities of

IFN-

and

is presumed to contribute to T H 1-like lymphocyte differ-

entiation. Its receptor includes the IL-12R

include only modest antiviral activity and its deriva-

tion primarily from T lymphocytes suggests that it may be

more of an interleukin than an interferon. IFN-

1 chain.

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-

marily distinguished from IL-2 through its use of a

unique

HUMORAL IMMUNITY

chain as part of its receptor signaling com-

plex. 14 Both receptors share the use of the

At least two cytokines contribute to B-lymphocyte

maturation in the bone marrow, the lymphoid stem cell

growth factors IL-7 and IL-11. IL-7 is critically important

to the development of B and T lymphocytes through its

production by stromal tissue of the bone marrow and thy-

mus, from which it interacts with lymphoid precursors. In

addition, IL-7 stimulates the proliferation and differentia-

tion of cytotoxic T and NK cells and stimulates the tumo-

ricidal activity of monocytes and macrophages.

After B cells egress from the bone marrow, isotype

switching, the activation of mature B cells into

immunoglobulin-secreting B cells, and their final differ-

entiation into plasma cells are processes that are under T-

cell control. 16 Cytokines that trigger isotype switching

include IL-4 and IL-13, which induces the IgE isotype,

TGF-

chain.

Mononuclear phagocytic cells, epithelium, fibroblasts,

and placenta are other sources of IL-15, whereas activat-

ed T lymphocytes, the most important source of IL-2, do

not express IL-15. As discussed later, like IL-2, IL-15 is

a T-cell growth factor, is chemotactic for T lymphocytes,

differentiates NK cells, and stimulates B-cell growth and

differentiation. IL-15 provides a mechanism by which

mononuclear phagocytic cells can regulate T- and NK-

cell proliferation and function in a fashion similar to T-

cell–derived IL-2.

and

CYTOTOXIC IMMUNITY

Immune responses directed against virus-infected and

neoplastic cells are primarily mediated by CD8 + cytotox-

ic lymphocytes and NK cells. Cytokines that activate

cytotoxic immunity include IL-2, IL-4, IL-5, IL-6, IL-7,

IL-10, IL-12, and IL-15—which are discussed else-

where—as well as IL-11 and, most importantly, TNF-

, which triggers IgA, and IL-10, which contributes

to the generation of IgG4. Other cytokines that influence

B-cell maturation include IFN-

, IL-1, IL-2, IL-5, IL-6,

IL-12, IL-15, and IL-21.

CELLULAR IMMUNITY

Interleukin-2

TNF-

, and the interferons.

Interleukin-11

IL-11 was originally described as a stimulatory factor

for hematopoietic precursor cells. It contributes to lym-

phoid production in the bone marrow and synergizes

with other growth factors to produce erythrocytes,

platelets, and mast cells. IL-11 stimulates the production

of acute phase proteins and induces lymphoid cell differ-

entiation. IL-11 is an important stimulatory factor for

connective tissue cells such as fibroblasts. A role for IL-

11 in asthma remodeling is suggested by studies demon-

strating expression of IL-11 in severe asthma, 15 and the

capacity of this cytokine to stimulate fibroblast prolifer-

ation and collagen deposition.

Stimulation of T cells by antigen in the presence

of accessory signals provided by the cytokines IL-1 and

IL-6 and the cognate interaction of the B7 molecules

(CD80 or CD88) with CD28 induces the simultaneous

secretion of IL-2 and the expression of high-affinity

IL-2R. Subsequently, the binding of secreted IL-2 to these

IL-2R–positive T cells induces clonal T-cell proliferation.

The requirement for both IL-2 production and IL-2R

expression for T-cell proliferation ensures that only T cells

specific for the antigen inciting the immune response

become activated. In addition to its role as a T-cell growth

factor, IL-2 is also involved in activation of NK cells, B

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-

Interleukin-4. In addition to T-helper lymphocytes, IL-

4 20 is derived from eosinophils, basophils, and possibly

mast cells. In both eosinophils and mast cells, IL-4 exists

as a preformed, granule-associated peptide and can be

rapidly released in allergic inflammatory responses. IL-4

stimulates MHC class II molecules, B7, CD40, surface

IgM, and low-affinity IgE receptor (CD23) expression by

B cells, thereby enhancing the antigen-presenting capac-

ity of B cells. IL-4 induces the immunoglobulin isotype

switch from IgM to IgE. 21,22 Other B-cell–activat-

ing cytokines, such as IL-2, IL-5, IL-6, and IL-9, syner-

gize with IL-4 to increase the secretion of IgE. IL-4 has

been identified in the serum, bronchoalveolar lavage

fluid, and lung tissue of asthmatic subjects, in nasal

polyp tissue, and in the nasal mucosa of subjects with

allergic rhinitis.

In addition to these effects on B cells, IL-4 has impor-

tant influences on T-lymphocyte growth, differentiation,

and survival, producing important influences on allergic

inflammation. As will be discussed later, IL-4 drives the

initial differentiation of naïve T-helper type 0 (T H 0) lym-

phocytes toward a T H 2 phenotype. IL-4 is also important

in maintaining allergic immune responses by preventing

apoptosis of T lymphocytes. 23 The production of IL-4 by

T H 2 lymphocytes renders these cells refractory to the

anti-inflammatory influences of corticosteroids.

Other activities of IL-4 include enhancing the expres-

sion of MHC molecules and low-affinity IgE receptors

(CD23) on macrophages. In contrast to these proinflam-

matory effects on monocytes, IL-4 downregulates anti-

body-dependent cellular cytotoxicity (ADCC), inhibits

expression of Fc receptors, inhibits their differentiation

into macrophages, and downregulates production of

nitric oxide, IL-1, IL-6, and TNF-

IL-21 is a newly described cytokine having homology

to both IL-2 and IL-15, which is predominantly produced

by activated T lymphocytes. 17 IL-21 receptors are

expressed on activated B, T, and NK cells. It shares

numerous biological activities with IL-2 and IL-15,

including the capacity to activate NK cells and promote

the proliferation of B and T lymphocytes.

The most important cytokine responsible for cell-

mediated immunity is IFN-

. 18 It is primarily produced by

T-helper lymphocytes but is also derived from cytotoxic T

cells and NK cells. IFN-

mediates increased MHC class

I and II molecule expression. IFN-

stimulates antigen

presentation and cytokine production by monocytes and

also stimulates monocyte effector functions, including

adherence, phagocytosis, secretion, the respiratory burst,

and nitric oxide production. The net result is the accumu-

lation of macrophages at the site of cellular immune

responses, with their activation into macrophages capable

of killing intracellular pathogens. In addition to its effects

on mononuclear phagocytes, IFN-

stimulates killing by

NK cells and neutrophils. It stimulates adherence of gran-

ulocytes to endothelial cells through the induction of

ICAM-1, an activity shared with IL-1 and TNF. As with

other interferons, IFN-

inhibits viral replication. As dis-

is an inhibitor of allergic responses

through its capacity to inhibit IL-4–mediated effects.

Interleukins-16 and -17

Additional cytokines that are secreted by T-helper lym-

phocytes and contribute to cell-mediated immunity are

TNF-

while stimulating

production of IL-1ra. Another important activity of IL-4

in allergic inflammation is its ability to induce expression

of VCAM-1 on endothelial cells. This produces

enhanced adhesiveness of endothelium for T cells,

eosinophils, basophils, and monocytes but not neu-

trophils, as is characteristic of allergic reactions. 24 IL-4

but not IL-13 receptors are present on mast cells, where

they function to stimulate IgE receptor expression. An

additional important influence of IL-4 on allergic inflam-

mation is its ability to induce mast cell expression of the

enzyme leukotriene C4 (LTC 4 ) synthase, thereby deter-

mining the capacity of mast cells to produce cysteinyl

leukotrienes. 25 IL-4 stimulates mucin production and

contributes to the excessive mucous production in the

asthmatic airway. Functional IL-4 receptors are het-

erodimers consisting of the IL-4R

,IL-4, IL-9, and IL-13, as well as by histamine. IL-

17 represents a family of cytokines that are expressed by

activated T cells predominantly of the memory phenotype

(CD4 + CD45RO + ) and also by eosinophils. IL-17 activates

macrophages, fibroblasts, and stromal cells, including

their expression of ICAM-1 and secretion of cytokines

(IL-6, IL-8, IL-11, granulocyte–colony stimulating factor

[G-CSF]), prostaglandin E 2 , and nitric oxide. IL-17

expression is increased in asthma, in which its ability to

activate fibroblasts suggests a role in airway remodeling.

ALLERGIC IMMUNITY

A final possible outcome of T-cell activation is the

development of allergic immunity. Several features

specifically associated with the asthmatic state are regu-

lated by cytokines. These include the regulation of IgE,

eosinophilia, and mast cell proliferation.

chain interacting

with the shared

chain or the IL-13R

1 chain. 26

The

chain by IL-13 and IL-4 and the

activation by this chain of the signaling protein Stat6

explains many of the common biological activities of

these two cytokines.

Interleukin-13. IL-13 is homologous to IL-4 and

shares much of its biological activities on mononuclear

Regulation of IgE

The inappropriate production of IgE in response to aller-

Interferon-

cussed later, IFN-

, IL-16, and IL-17. IL-16 is a T-cell–derived prod-

uct that is chemotactic for CD4 + lymphocytes,

eosinophils, and monocytes and uses the CD4 molecule

as its receptor. 19 Its production is upregulated by TNF-

TGF-

shared use of the IL-4R

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