antiinflammatory cytokines.pdf

Anti-Inflammatory Cytokines

Steven M. Opal and Vera A. DePalo

Chest

2000;117;1162-1172

DOI: 10.1378/chest.117.4.1162

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impact of basic research on tomorrow’s

medicine

Anti-Inflammatory Cytokines*

Steven M. Opal, MD; and Vera A. DePalo, MD

The anti-inflammatory cytokines are a series of immunoregulatory molecules that control the

proinflammatory cytokine response. Cytokines act in concert with specific cytokine inhibitors and

soluble cytokine receptors to regulate the human immune response. Their physiologic role in

inflammation and pathologic role in systemic inflammatory states are increasingly recognized.

Major anti-inflammatory cytokines include interleukin (IL)-1 receptor antagonist, IL-4, IL-6,

IL-10, IL-11, and IL-13. Specific cytokine receptors for IL-1, tumor necrosis factor-

(CHEST 2000; 117:1162–1172)

Key words: anti-inflammatory cytokines; cytokines; inflammation; sepsis; septic shock

Abbreviations: GM-CSF

granulocyte-macrophage colony-stimulating factor; IFN-

interferon-

;IL

interleukin;

IL-1ra

IL-1

receptor

antagonist;

LPS

lipopolysaccharide;

MHC

major

histocompatibility

complex;

MIP

macrophage inflammatory protein; NF-

nuclear factor

B; TGF-

transforming growth factor-

;Th

helper cells; TNF

tumor necrosis factor

highly complex and intricate network of control

elements. Prominent among these regulatory com-

ponents are the anti-inflammatory cytokines and

specific cytokine inhibitors. Under physiologic con-

ditions, these cytokine inhibitors serve as immuno-

modulatory elements that limit the potentially inju-

rious effects of sustained or excess inflammatory

reactions. Under pathologic conditions, these anti-

inflammatory mediators may either (1) provide in-

sufficient control over proinflammatory activities in

immune-mediated diseases or (2) overcompensate

and inhibit the immune response, rendering the host

at risk from systemic infection. 1,2

A dynamic and ever-shifting balance exists be-

tween proinflammatory cytokines and anti-inflam-

matory components of the human immune system.

The regulation of inflammation by these cytokines

and cytokine inhibitors is complicated by the fact

that the immune system has redundant pathways

with multiple elements having similar physiologic

effects. Furthermore, with the potential exception of

interleukin (IL)-1 receptor antagonist (IL-1ra), all

the anti-inflammatory cytokines have at least some

proinflammatory properties as well. The net effect of

any cytokine is dependent on the timing of cytokine

release, the local milieu in which it acts, the presence

of competing or synergistic elements, cytokine re-

ceptor density, and tissue responsiveness to each

cytokine. 3 This is what makes the study of cytokine

biology so fascinating (and so frustrating as well!).

Perturbations of this regulatory network of cyto-

kines by genetic, environmental, or microbial ele-

ments may have highly deleterious consequences. 4–8

The major anti-inflammatory cytokines and their

specific roles in human disease will be the focus of

this brief review. These inhibitory cytokines have

already proven to be efficacious in a variety of

clinical conditions marked by excess inflammation.

Their potential therapeutic use in numerous other

inflammatory states will also be described.

The principal anti-inflammatory cytokines and cy-

tokine inhibitors are listed in Tables 1, 2. The

functional definition of an anti-inflammatory cyto-

kine in this review is the ability of the cytokine to

inhibit the synthesis of IL-1, tumor necrosis factor

(TNF), and other major proinflammatory cytokines.

* From the Infectious Disease Division and Critical Care Divi-

sion, Brown University School of Medicine, Providence, RI.

Manuscript received September 30, 1999; revision accepted

October 1, 1999.

Correspondence to: Steven M. Opal, MD, Infectious Disease

Division, Memorial Hospital of Rhode Island, 111 Brewster St,

Pawtucket, RI 02860; e-mail: Steven_Opal@brown.edu

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, and IL-18

also function as proinflammatory cytokine inhibitors. The nature of anti-inflammatory cytokines

and soluble cytokine receptors is the focus of this review. The current and future therapeutic uses

of these anti-inflammatory cytokines are also reviewed.

T he human immune response is regulated by a

Table 1— Cytokines With Anti-inflammatory Activities *

Cytokines

Cellular Sources

Major Activities

IL-1ra

Monocyte/macrophage dendritic cells

Specific inhibitor of IL-1

- and IL-1

-mediated cellular activation

at the IL-1 cellular receptor level

IL-4

T cells (Th2), mast cells, B cells, stromal cells

Promotes Th2 lymphocyte development; inhibition of LPS-

induced proinflammatory cytokine synthesis

IL-6

T cells, B cells, monocytes, PMNs

Inhibition of TNF and IL-1 production by macrophages

IL-10

Monocyte/macrophage, T cells (Th2), B cells

Inhibition of monocyte/macrophage and neutrophil cytokine

production and inhibition of Th1-type lymphocyte responses

IL-11

Stromal cells, fibroblasts

Inhibits proinflammatory cytokine response by

monocyte/macrophages and promotes Th2 lymphocyte response

IL-13

T cells (Th2)

Shares homology with IL-4 and shares IL-4 receptor; attenuation

of monocyte/macrophage function

TGF-

Constitutively expressed in many cell lines

Inhibition of monocyte/macrophage MHC class II expression and

proinflammatory cytokine synthesis

*PMN

polymorphonuclear cell.

Table 2— Soluble Cytokine Receptors With Anti-inflammatory Activities

Soluble Receptor

Cellular Sources

Major Activities

Soluble TNF receptor p55

(sTNFRI or sTNFRp55)

Multiple cell lines

Binds to TNF trimers in the circulation, preventing membrane-bound

TNF receptor–TNF ligand interactions

Soluble TNF receptor p75

(sTNFRII or sTNFRp75)

Multiple cell lines

Binds to TNF trimers in the circulation, preventing membrane-bound

TNF receptor–TNF ligand interactions

Soluble IL-1 receptor type 2

(sIL-1RII)

B cells, neutrophils, bone

marrow precursors

Binds to circulating IL-1 ligands in the plasma, preventing IL-1

from binding to the IL-1 receptor type 1

Membrane-bound IL-1

receptor type 2 (mIL-1RII)

B cells, neutrophils, bone

marrow precursors

Decoy receptor that lacks intracellular signaling function and

competes with type 1 IL-1R for IL-1 ligand binding at the cell

membrane

IL-18 binding protein

(IL-18BP)

Splenocytes, multiple

other cell lines

Soluble extracellular domain of IL-18 receptor that functions as a

decoy receptor and binds circulating IL-18

T helper (Th) lymphocytes can differentiate

into functionally dichotomous subsets of Th cells

depending on the microenvironment of the cell. The

cytokine-producing CD4

MAJOR ANTI-INFLAMMATORY CYTOKINES

IL-1ra

helper cells are classified

into Th1- and Th2-type cells on the basis of the

cytokines produced. 9,10 A similar functional system

has been recently described with CD8

IL-1ra is a 152-amino-acid protein that functions

as a specific inhibitor of the two other functional

members of the IL-1 family, IL-1

. 3,12

The human gene for IL-1ra is on the long arm of

chromosome 2 in close proximity to the genes for

IL-1

and IL-1

cytotoxic T

T2 cells). 11

Th1-type cells secrete high levels of IL-2, TNF-

T1 and CD8

. Genetic evidence indicates that

IL-1ra diverged from an ancestral IL-1 gene as a

partial duplication event early in vertebrate evolu-

tion. 12,13 IL-1ra shares approximately 26% amino

acid sequence homology with IL-1

and IL-1

). This activates macro-

phages and promotes cell-mediated immune re-

sponses against invasive intracellular pathogens.

Th2-type cells produce a variety of anti-inflamma-

tory cytokines, including IL-4, IL-5, IL-6, IL-10, and

IL-13. Both Th1 and Th2 cells produce lesser

amounts of TNF-

(IFN-

and 19% homol-

. A three-dimensional structure of

IL-1ra is similar to IL-1

and IL-1

and exists as a

, granulocyte-macrophage colony-

stimulating factor (GM-CSF), and IL-3. Th2-type

cytokines promote humoral immune responses

against extracellular pathogens. Mutual cross inhibi-

tion between Th1- and Th2-type cytokines polarize

functional Th cell responses into cell-mediated or

humoral immune responses. Regulation of T-cell

activation by the anti-inflammatory cytokines is a

crucial early control element in this process (Fig 1).

series of anti-parallel

chains held in a tight

barrel

configuration. 13

IL-1ra blocks the action of IL-1

functional ligands by competitive inhibition at the

IL-1 receptor level. IL-1ra binds with equal or

greater affinity than does IL-1

and IL-1

to the

type 1 (80 kd) membrane-bound IL-1 receptor.

IL-1ra does not bind with high affinity to the type II

(68 kd) IL-1 receptor. 14,15

and IL-1

After attachment of IL-1

CHEST / 117/4/APRIL, 2000 1163

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CD4

cells (CD8

and interferon-

ogy with IL-1

Th cells and the role of the

anti-inflammatory cytokines in T-cell differentiation. Solid lines indicate stimulatory pathways, and

dotted lines indicate inhibitory pathways. APC

antigen-presenting cell; Th 0

uncommitted CD4

Th cell precursor. (See Mosmann et al 9 for review.)

to its receptor, intracellular signaling occurs after a

heterodimeric complex is formed between the type 1

receptor and an essential second protein known as

IL-1 receptor-accessory protein. 16 IL-1ra will bind

with high affinity to the type 1 IL-1 receptor but fails

to engage the IL-1 receptor accessory protein. This

occupies the membrane-bound IL-1 receptor bind-

ing site and prevents cellular activation by IL-1

synthesis has been shown to increase susceptibility to

diverse human pathogens such as Lyme arthritis,

tuberculosis, and a variety of other infectious diseas-

es. 19 –21 Conversely, inadequate local IL-1ra synthe-

sis in the lung may predispose to severe acute lung

injury and result in excess lethality in ARDS. 6

Because IL-1 is such a prominent proinflamma-

tory cytokine in a multitude of systemic inflamma-

tory states, IL-1ra has been extensively studied in

clinical trials as a specific IL-1 inhibitor. Despite

convincing evidence that IL-1 plays an important

role in the pathogenesis of bacterial sepsis, 22,23 the

results of IL-1ra therapy in large phase III clinical

trials for severe sepsis have been disappointing. 24

Nonetheless, IL-1ra continues to be a promising new

treatment for the management of patients with

refractory forms of rheumatoid arthritis (Table 3). 25

or IL-1

by steric inhibition. 17

IL-1ra is produced by monocytes and macro-

phages and is released into the systemic circulation

after

lipopolysaccharide (LPS) stimulation in human vol-

unteers. 3

100-fold excess than either IL-1

or IL-1

are

differentially regulated at their own promoter sites.

Although bacterial LPS stimulates the synthesis of

both IL-1

The synthesis of IL-1ra and IL-1

and IL-1ra, other stimuli cause differen-

tial release of IL-1ra and IL-1

. The anti-inflamma-

tory cytokines IL-4, IL-6, IL-10, and IL-13 inhibit

the synthesis of IL-1

, yet they stimulate the syn-

thesis of IL-1ra. 14

There is at least one important polymorphism in

the genetic regulation of IL-1ra synthesis in human

populations. 18 A regulatory region located in intron 2

of the IL-1ra gene varies depending on the number

of tandem duplications of an 86-base pair direct-

repeat sequence. DNA polymorphisms at this site

may determine the synthetic rate of IL-1ra and alter

IL-4

IL-4 is a highly pleiotropic cytokine that is able to

influence Th cell differentiation. Early secretion of

IL-4 leads to polarization of Th cell differentiation

toward Th2-like cells. 9 Th2-type cells secrete their

own IL-4, and subsequent autocrine production of

IL-4 supports cell proliferation. The Th2- cell secre-

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FIGURE 1. The polarization of Th1 and Th2 responses by CD4

the host response to inflammatory stimuli. Excess

IL-1ra synthesis in relationship to IL-1

IL-1

Table 3— Current and Future Therapeutic Uses for

Anti-inflammatory Cytokines and Soluble Cytokine

Inhibitors *

infections is not adequately defined and will neces-

sitate additional clinical investigation.

IL-4 is able to affect a variety of structural cells. It

can potentiate proliferation of vascular endothelium

and skin fibroblasts yet decrease proliferation of

adult human astrocytes and vascular smooth muscle

cells. 26,34 In addition, IL-4 induces a potent cytotoxic

response against tumors. 35,36 In a study of 63 patients

with stage IV non-small cell lung cancer, data on

treatment with recombinant human IL-4 seemed to

suggest a possible dose-related response. 37 IL-4 may

act by stabilizing disease and modifying tumor

growth rates in addition to inducing tumor shrinkage

and cell death without causing severe side effects,

suggesting a possible adjuvant role for IL-4 in the

treatment of malignant diseases.

Cytokine/Soluble

Cytokine Receptor

Clinical Indications

IL-1ra

Rheumatoid arthritis (phase II/III

clinical trials)

IL-10

Prevention of acute lung injury (phase

I clinical trials); gut ischemia-

reperfusion injury (phase I clinical

trials); inflammatory bowel disease

(phase II clinical trials); rheumatoid

arthritis (phase II clinical trials);

psoriasis, multiple sclerosis (early

phase II clinical trials)

IL-11

Chemotherapy-induced

thrombocytopenia (approved

indication); inflammatory bowel

disease (phase II clinical trials);

chemotherapy-induced mucositis

(phase II clinical trials); psoriasis

(phase I clinical trials)

IL-6

IL-6 has long been regarded as a proinflammatory

cytokine induced by LPS along with TNF-

TNFR (p75):Fc

fusion protein

Treatment of rheumatoid arthritis

(approved indication)

and

IL-1. IL-6 is often used as a marker for systemic

activation of proinflammatory cytokines. 38 Like many

other cytokines, IL-6 has both proinflammatory and

anti-inflammatory properties. Although IL-6 is a

potent inducer of the acute-phase protein response,

it has anti-inflammatory properties as well. 39 Recent

evidence generated from IL-6 knockout mice has

demonstrated that IL-6, like other members of the

gp130 receptor ligand family, acts predominantly as

an anti-inflammatory cytokine. After binding to its

specific

*TNFR

TNF receptor.

tion of IL-4 and IL-10 leads to the suppression of

Th1 responses by down-regulating the production of

macrophage-derived IL-12 26 and inhibiting the dif-

ferentiation of Th1-type cells. 9,10

IL-4 is a 20-kd glycoprotein produced by mature

Th2 cells and cells from the mast cell or basophil

lineage. IL-4 drives Th2 responses, mediates the

recruitment and activation of mast cells, and stimu-

lates the production of IgE antibodies via the differ-

entiation of B cells into IgE-secreting cells. 26,27

IL-4 has marked inhibitory effects on the expres-

sion and release of the proinflammatory cytokines. It

is able to block or suppress the monocyte-derived

cytokines, including IL-1, TNF-

receptor, IL-6 complexes with the ubiqui-

tous gp130 signal transducing unit. IL-6 belongs to a

family of gp130 receptor ligands that includes IL-11,

leukemia inhibitory factor, ciliary neurotrophic fac-

tor, oncostatin M, and cardiotrophin-1. Inasmuch as

these peptide molecules use a common cellular

receptor, they share many of the physiologic features

attributable to IL-6. IL-6 down-regulates the synthe-

sis of IL-1 and TNF. 40,41 IL-6 attenuates the synthe-

sis of the proinflammatory cytokines while having

little effect on the synthesis of anti-inflammatory

cytokines such as IL-10 and transforming growth

factor-

, IL-6, IL-8, and

macrophage inflammatory protein (MIP)-1

. 26 –29 It

has also been shown to suppress macrophage cyto-

toxic activity, parasite killing, and macrophage-de-

rived nitric oxide production. 30 In contrast to its

inhibitory effects on the production of proinflamma-

tory cytokines, it stimulates the synthesis of the

cytokine inhibitor IL-1ra. 31

The immunologic effects of IL-4 in the presence

of bacterial infection are complex and incompletely

understood. IL-4 has been shown to enhance clear-

ance of Pseudomonas aeruginosa from lung tissue in

experimental models of Gram-negative bacterial

pneumonia. 32 In Gram-positive bacterial infection

models, IL-4 has been found to act as a growth factor

for Staphylococcus aureus , resulting in systemic in-

fection and increased lethality from bacterial sep-

sis. 33

). IL-6 induces the synthesis of

glucocorticoids 42 and promotes the synthesis of IL-

1ra and soluble TNF receptor release in human

volunteers. 43 At the same time, IL-6 inhibits the

production of proinflammatory cytokines such as

GM-CSF, IFN-

(TGF-

, and MIP-2. 38 The net result of

these immunologic effects place IL-6 among the

anti-inflammatory cytokine group.

IL-10

The role of IL-4 in the presence of systemic

IL-10 is the most important anti-inflammatory

cytokine found within the human immune response.

It is a potent inhibitor of Th1 cytokines, including

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