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-␣, 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. (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-␬B ⫽ nuclear factor ␬B; TGF-␤ ⫽ transforming growth factor-␤; Th ⫽ T
helper cells; TNF ⫽ tumor necrosis factor

T hehighlyhuman immune response is regulated by a

complex and intricate network of control
with multiple elements having similar physiologic
effects. Furthermore, with the potential exception of
elements. Prominent among these regulatory com- interleukin (IL)-1 receptor antagonist (IL-1ra), all
ponents are the anti-inflammatory cytokines and the anti-inflammatory cytokines have at least some
specific cytokine inhibitors. Under physiologic con- proinflammatory properties as well. The net effect of
ditions, these cytokine inhibitors serve as immuno- any cytokine is dependent on the timing of cytokine
modulatory elements that limit the potentially inju- release, the local milieu in which it acts, the presence
rious effects of sustained or excess inflammatory of competing or synergistic elements, cytokine re-
reactions. Under pathologic conditions, these anti- ceptor density, and tissue responsiveness to each
inflammatory mediators may either (1) provide in- cytokine.3 This is what makes the study of cytokine
sufficient control over proinflammatory activities in biology so fascinating (and so frustrating as well!).
immune-mediated diseases or (2) overcompensate Perturbations of this regulatory network of cyto-
and inhibit the immune response, rendering the host kines by genetic, environmental, or microbial ele-
at risk from systemic infection.1,2 ments may have highly deleterious consequences.4 – 8
A dynamic and ever-shifting balance exists be- The major anti-inflammatory cytokines and their
tween proinflammatory cytokines and anti-inflam- specific roles in human disease will be the focus of
matory components of the human immune system. this brief review. These inhibitory cytokines have
already proven to be efficacious in a variety of
The regulation of inflammation by these cytokines
clinical conditions marked by excess inflammation.
and cytokine inhibitors is complicated by the fact
Their potential therapeutic use in numerous other
that the immune system has redundant pathways
inflammatory states will also be described.
The principal anti-inflammatory cytokines and cy-
*From the Infectious Disease Division and Critical Care Divi-
sion, Brown University School of Medicine, Providence, RI. tokine inhibitors are listed in Tables 1, 2. The
Manuscript received September 30, 1999; revision accepted functional definition of an anti-inflammatory cyto-
October 1, 1999. kine in this review is the ability of the cytokine to
Correspondence to: Steven M. Opal, MD, Infectious Disease
Division, Memorial Hospital of Rhode Island, 111 Brewster St, inhibit the synthesis of IL-1, tumor necrosis factor
Pawtucket, RI 02860; e-mail: Steven_Opal@brown.edu (TNF), and other major proinflammatory cytokines.

1162 Impact of Basic Research on Tomorrow’s Medicine

 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 Multiple cell lines Binds to TNF trimers in the circulation, preventing membrane-bound
(sTNFRI or sTNFRp55) TNF receptor–TNF ligand interactions
Soluble TNF receptor p75 Multiple cell lines Binds to TNF trimers in the circulation, preventing membrane-bound
(sTNFRII or sTNFRp75) TNF receptor–TNF ligand interactions
Soluble IL-1 receptor type 2 B cells, neutrophils, bone Binds to circulating IL-1 ligands in the plasma, preventing IL-1␤
(sIL-1RII) marrow precursors from binding to the IL-1 receptor type 1
Membrane-bound IL-1 B cells, neutrophils, bone Decoy receptor that lacks intracellular signaling function and
receptor type 2 (mIL-1RII) marrow precursors competes with type 1 IL-1R for IL-1 ligand binding at the cell
membrane
IL-18 binding protein Splenocytes, multiple Soluble extracellular domain of IL-18 receptor that functions as a
(IL-18BP) other cell lines decoy receptor and binds circulating IL-18

CD4⫹ T helper (Th) lymphocytes can differentiate Major Anti-inflammatory Cytokines

into functionally dichotomous subsets of Th cells IL-1ra
depending on the microenvironment of the cell. The
cytokine-producing CD4⫹ helper cells are classified IL-1ra is a 152-amino-acid protein that functions
into Th1- and Th2-type cells on the basis of the as a specific inhibitor of the two other functional
cytokines produced.9,10 A similar functional system members of the IL-1 family, IL-1␣ and IL-1␤.3,12
has been recently described with CD8⫹ cytotoxic T The human gene for IL-1ra is on the long arm of
cells (CD8⫹ T1 and CD8⫹ T2 cells).11 chromosome 2 in close proximity to the genes for
Th1-type cells secrete high levels of IL-2, TNF-␣, IL-1␣ and IL-1␤. Genetic evidence indicates that
and interferon-␥ (IFN-␥). This activates macro- IL-1ra diverged from an ancestral IL-1 gene as a
phages and promotes cell-mediated immune re- partial duplication event early in vertebrate evolu-
sponses against invasive intracellular pathogens. tion.12,13 IL-1ra shares approximately 26% amino
Th2-type cells produce a variety of anti-inflamma- acid sequence homology with IL-1␤ and 19% homol-
tory cytokines, including IL-4, IL-5, IL-6, IL-10, and ogy with IL-1␣. A three-dimensional structure of
IL-13. Both Th1 and Th2 cells produce lesser IL-1ra is similar to IL-1␣ and IL-1␤ and exists as a
amounts of TNF-␣, granulocyte-macrophage colony- series of anti-parallel ␤ chains held in a tight ␤ barrel
stimulating factor (GM-CSF), and IL-3. Th2-type configuration.13
cytokines promote humoral immune responses IL-1ra blocks the action of IL-1␣ and IL-1␤
against extracellular pathogens. Mutual cross inhibi- functional ligands by competitive inhibition at the
tion between Th1- and Th2-type cytokines polarize IL-1 receptor level. IL-1ra binds with equal or
functional Th cell responses into cell-mediated or greater affinity than does IL-1␣ and IL-1␤ to the
humoral immune responses. Regulation of T-cell type 1 (80 kd) membrane-bound IL-1 receptor.
activation by the anti-inflammatory cytokines is a IL-1ra does not bind with high affinity to the type II
crucial early control element in this process (Fig 1). (68 kd) IL-1 receptor.14,15 After attachment of IL-1

CHEST / 117 / 4 / APRIL, 2000 1163

 Figure 1. The polarization of Th1 and Th2 responses by CD4⫹ 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; Th0 ⫽ uncommitted CD4⫹
Th cell precursor. (See Mosmann et al9 for review.)

to its receptor, intracellular signaling occurs after a the host response to inflammatory stimuli. Excess
heterodimeric complex is formed between the type 1 IL-1ra synthesis in relationship to IL-1␣ or IL-1␤
receptor and an essential second protein known as synthesis has been shown to increase susceptibility to
IL-1 receptor-accessory protein.16 IL-1ra will bind diverse human pathogens such as Lyme arthritis,
with high affinity to the type 1 IL-1 receptor but fails tuberculosis, and a variety of other infectious diseas-
to engage the IL-1 receptor accessory protein. This es.19 –21 Conversely, inadequate local IL-1ra synthe-
occupies the membrane-bound IL-1 receptor bind- sis in the lung may predispose to severe acute lung
ing site and prevents cellular activation by IL-1␣ or injury and result in excess lethality in ARDS.6
IL-1␤ by steric inhibition.17 Because IL-1 is such a prominent proinflamma-
IL-1ra is produced by monocytes and macro- tory cytokine in a multitude of systemic inflamma-
phages and is released into the systemic circulation tory states, IL-1ra has been extensively studied in
in ⬎ 100-fold excess than either IL-1␣ or IL-1␤ after clinical trials as a specific IL-1 inhibitor. Despite
lipopolysaccharide (LPS) stimulation in human vol- convincing evidence that IL-1 plays an important
unteers.3 The synthesis of IL-1ra and IL-1␤ are role in the pathogenesis of bacterial sepsis,22,23 the
differentially regulated at their own promoter sites. results of IL-1ra therapy in large phase III clinical
Although bacterial LPS stimulates the synthesis of trials for severe sepsis have been disappointing.24
both IL-1␤ and IL-1ra, other stimuli cause differen- Nonetheless, IL-1ra continues to be a promising new
tial release of IL-1ra and IL-1␤. The anti-inflamma- treatment for the management of patients with
tory cytokines IL-4, IL-6, IL-10, and IL-13 inhibit refractory forms of rheumatoid arthritis (Table 3).25
the synthesis of IL-1␤, yet they stimulate the syn-
thesis of IL-1ra.14
IL-4
There is at least one important polymorphism in
the genetic regulation of IL-1ra synthesis in human IL-4 is a highly pleiotropic cytokine that is able to
populations.18 A regulatory region located in intron 2 influence Th cell differentiation. Early secretion of
of the IL-1ra gene varies depending on the number IL-4 leads to polarization of Th cell differentiation
of tandem duplications of an 86-base pair direct- toward Th2-like cells.9 Th2-type cells secrete their
repeat sequence. DNA polymorphisms at this site own IL-4, and subsequent autocrine production of
may determine the synthetic rate of IL-1ra and alter IL-4 supports cell proliferation. The Th2- cell secre-

1164 Impact of Basic Research on Tomorrow’s Medicine

 Table 3—Current and Future Therapeutic Uses for infections is not adequately defined and will neces-
Anti-inflammatory Cytokines and Soluble Cytokine sitate additional clinical investigation.
Inhibitors*
IL-4 is able to affect a variety of structural cells. It
Cytokine/Soluble can potentiate proliferation of vascular endothelium
Cytokine Receptor Clinical Indications and skin fibroblasts yet decrease proliferation of
IL-1ra Rheumatoid arthritis (phase II/III adult human astrocytes and vascular smooth muscle
clinical trials) cells.26,34 In addition, IL-4 induces a potent cytotoxic
IL-10 Prevention of acute lung injury (phase response against tumors.35,36 In a study of 63 patients
I clinical trials); gut ischemia- with stage IV non-small cell lung cancer, data on
reperfusion injury (phase I clinical
trials); inflammatory bowel disease
treatment with recombinant human IL-4 seemed to
(phase II clinical trials); rheumatoid suggest a possible dose-related response.37 IL-4 may
arthritis (phase II clinical trials); act by stabilizing disease and modifying tumor
psoriasis, multiple sclerosis (early growth rates in addition to inducing tumor shrinkage
phase II clinical trials) and cell death without causing severe side effects,
IL-11 Chemotherapy-induced
thrombocytopenia (approved
suggesting a possible adjuvant role for IL-4 in the
indication); inflammatory bowel treatment of malignant diseases.
disease (phase II clinical trials);
chemotherapy-induced mucositis IL-6
(phase II clinical trials); psoriasis
(phase I clinical trials) IL-6 has long been regarded as a proinflammatory
TNFR (p75):Fc Treatment of rheumatoid arthritis cytokine induced by LPS along with TNF-␣ and
fusion protein (approved indication) IL-1. IL-6 is often used as a marker for systemic
*TNFR ⫽ TNF receptor. 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,
tion of IL-4 and IL-10 leads to the suppression of
it has anti-inflammatory properties as well.39 Recent
Th1 responses by down-regulating the production of
evidence generated from IL-6 knockout mice has
macrophage-derived IL-1226 and inhibiting the dif-
demonstrated that IL-6, like other members of the
ferentiation of Th1-type cells.9,10
gp130 receptor ligand family, acts predominantly as
IL-4 is a 20-kd glycoprotein produced by mature
an anti-inflammatory cytokine. After binding to its
Th2 cells and cells from the mast cell or basophil
specific ␣ receptor, IL-6 complexes with the ubiqui-
lineage. IL-4 drives Th2 responses, mediates the
tous gp130 signal transducing unit. IL-6 belongs to a
recruitment and activation of mast cells, and stimu-
family of gp130 receptor ligands that includes IL-11,
lates the production of IgE antibodies via the differ-
leukemia inhibitory factor, ciliary neurotrophic fac-
entiation of B cells into IgE-secreting cells.26,27
tor, oncostatin M, and cardiotrophin-1. Inasmuch as
IL-4 has marked inhibitory effects on the expres-
these peptide molecules use a common cellular
sion and release of the proinflammatory cytokines. It
receptor, they share many of the physiologic features
is able to block or suppress the monocyte-derived
attributable to IL-6. IL-6 down-regulates the synthe-
cytokines, including IL-1, TNF-␣, IL-6, IL-8, and
sis of IL-1 and TNF.40,41 IL-6 attenuates the synthe-
macrophage inflammatory protein (MIP)-1␣.26 –29 It
sis of the proinflammatory cytokines while having
has also been shown to suppress macrophage cyto-
little effect on the synthesis of anti-inflammatory
toxic activity, parasite killing, and macrophage-de-
cytokines such as IL-10 and transforming growth
rived nitric oxide production.30 In contrast to its
factor-␤ (TGF-␤). IL-6 induces the synthesis of
inhibitory effects on the production of proinflamma-
glucocorticoids42 and promotes the synthesis of IL-
tory cytokines, it stimulates the synthesis of the
1ra and soluble TNF receptor release in human
cytokine inhibitor IL-1ra.31
volunteers.43 At the same time, IL-6 inhibits the
The immunologic effects of IL-4 in the presence
production of proinflammatory cytokines such as
of bacterial infection are complex and incompletely
GM-CSF, IFN-␥, and MIP-2.38 The net result of
understood. IL-4 has been shown to enhance clear-
these immunologic effects place IL-6 among the
ance of Pseudomonas aeruginosa from lung tissue in
anti-inflammatory cytokine group.
experimental models of Gram-negative bacterial
pneumonia.32 In Gram-positive bacterial infection
IL-10
models, IL-4 has been found to act as a growth factor
for Staphylococcus aureus, resulting in systemic in- IL-10 is the most important anti-inflammatory
fection and increased lethality from bacterial sep- cytokine found within the human immune response.
sis.33 The role of IL-4 in the presence of systemic It is a potent inhibitor of Th1 cytokines, including

CHEST / 117 / 4 / APRIL, 2000 1165

both IL-2 and IFN-␥. This activity accounts for its cates that endogenous concentrations of IL-10 are
initial designation as cytokine synthesis inhibition important in limiting the inflammatory response to
factor.44 – 46 In addition to its activity as a Th2 gut-associated bacteria. For this reason, IL-10 is in
lymphocyte cytokine, IL-10 is also a potent deacti- clinical trials as an anti-inflammatory therapy for
vator of monocyte/macrophage proinflammatory cy- inflammatory bowel disease among other potential
tokine synthesis.47,48 IL-10 is primarily synthesized indications (Table 3).
by CD4⫹ Th2 cells, monocytes, and B cells and
circulates as a homodimer consisting of two tightly IL-11
packed 160-amino-acid proteins.45,46 After engaging
IL-11 is a 178-amino-acid nonglycosylated peptide
its high-affinity 110-kd cellular receptor, IL-10 in-
cytokine that was initially isolated from the hemato-
hibits monocyte/macrophage-derived TNF-␣, IL-1,
poietic microenvironment.63 IL-11 shares many
IL-6, IL-8, IL-12, granulocyte colony-stimulating
properties of IL-6, including the common use of the
factor, MIP-1␣, and MIP-2␣.48 –50 IL-10 inhibits cell
gp130 receptor ligand complex as a signal transduc-
surface expression of major histocompatibility com-
tion pathway. IL-11 binds to its own unique IL-11 ␣
plex class II molecules, B7 accessory molecules, and
receptor and then complexes with gp130 cell mem-
the LPS recognition and signaling molecule CD14.46
branes of target cells.64 IL-11 was initially described
It also inhibits cytokine production by neutrophils
as a hematopoietic growth factor with particular
and natural killer cells. IL-10 inhibits nuclear factor
activity in the stimulation of thrombopoiesis. IL-11
␬B (NF-␬B) nuclear translocation after LPS stimu-
has recently been approved for clinical use as a
lation48 and promotes degradation of messenger
platelet restorative agent after chemotherapy-in-
RNA for the proinflammatory cytokines.46 In addi-
duced bone marrow suppression.65
tion to these activities, IL-10 attenuates surface
It has become clear that IL-11 has important
expression of TNF receptors and promotes the
immunoregulatory activities separate from its hema-
shedding of TNF receptors into the systemic circu-
topoietic growth factor potential. IL-11 has been
lation.51,52
shown to attenuate IL-1 and TNF synthesis from
IL-10 is readily measurable in the circulation in
macrophages by up-regulating inhibitory NF-␬B (in-
patients with systemic illnesses and a variety of
hibitory NF-␬B) synthesis in monocyte/macrophage
inflammatory states.53,54 IL-10 is present in sufficient
cell lines. Inhibitory NF-␬B prevents NF-␬B from
concentrations to have a physiologic impact on host
translocating to the nucleus where NF-␬B functions
responses to systemic inflammation. It has been
as a transcriptional activator for the proinflammatory
determined that patients who preferentially express
cytokines.66
high levels of IL-10 and reduced levels of TNF-␣ are
IL-11 has also been shown to inhibit the synthesis
more likely to die from meningococcemia55,56 and a
of IFN-␥ and IL-2 by CD4⫹ T cells. IL-11 functions
variety of other community-acquired infections.57
as a Th2-type cytokine, with induction of IL-4 and
Physiologically inadequate IL-10 responses after
inhibition of Th1-type cytokines.67 IL-11 does not
systemic injury may have detrimental consequences
induce the synthesis of IL-10 or TGF-␤. This indi-
as well. Low lung concentrations of IL-10 in patients
cates that IL-11 is a direct inhibitor of Th1 lympho-
with acute lung injury indicate that ARDS is more
cytes and does not act indirectly through induction of
likely to develop.6 The administration of IL-10 in
IL-10. IL-11 is rarely measurable in the systemic
experimental animal models of endotoxemia im-
circulation but has been detected and is physiologi-
proves survival.50 Human volunteers given IL-10
cally active in localized areas of inflammation, such
after endotoxin challenge suffer fewer systemic
as inflammatory arthritis or inflammatory bowel dis-
symptoms, neutrophil responses, and cytokine pro-
ease.68 IL-11 is currently in clinical trials as an
duction than placebo-treated control subjects.58
immunomodulator for a number of potential clinical
Moreover, mice who have genetic deletions of the
indications (Table 3).
IL-10 gene are more susceptible to endotoxin-in-
duced shock than normal mice.59 IL-10 generally
IL-13
protects the host from systemic inflammation after
toxin-induced injury, but renders the host suscepti- IL-13, a potent in vitro modulator of human
ble to lethality from overwhelming infection in a monocytes and B-cell function, is secreted by acti-
variety of experimental studies.60,61 This observation vated T lymphocytes.69,70 It is a 132-amino-acid
should be kept in mind when administering anti- nonglycosylated protein with a molecular weight of
inflammatory cytokines in clinical medicine. about 10 kd. The human IL-13 gene has been
The IL-10 knockout mouse spontaneously devel- mapped in close proximity to the IL-4 gene along a
ops a chronic inflammatory enteritis that mimics 4.5-kilobase sequence of DNA on chromosome
inflammatory bowel disease in humans.62 This indi- 5q31, suggesting a common ancestral origin.71 IL-13

1166 Impact of Basic Research on Tomorrow’s Medicine

and IL-4 share a common cellular receptor (IL-4 anti-inflammatory effects. It functions as a biological
type 1 receptor), and this accounts for many of the switch, antagonizing or modifying the action of other
similarities between these two anti-inflammatory cy- cytokines or growth factors. The presence of other
tokines.72 IL-4 and IL-13 share only 20% to 25% cytokines may modulate the cellular response to
primary amino acid homology, but the major ␣-he- TGF-␤, and the effect may differ depending on the
lical regions that are essential for their activity are activation state of the cell.80 TGF-␤ is capable of
highly homologous.69 The principal functional differ- converting an active site of inflammation into one
ence between IL-4 and IL-13 lies in their effects on dominated by resolution and repair.81 TGF-␤ often
T cells. IL-4 is a dominant mediator of Th2 cell exhibits disparate effects with immune-enhancing
differentiation, proliferation, and activity, whereas activity in local tissues and immune-suppressive ac-
IL-13 has minimal effects on T-cell function.70 tivity in the systemic circulation.
IL-13 can down-regulate the production of TNF, TGF-␤1 suppresses the proliferation and differen-
IL-1, IL-8, and MIP-1␣ by monocytes69,70 and has tiation of T cells and B cells and limits IL-2, IFN-␥,
profound effects on expression of surface molecules and TNF production. TGF-␤1 acts as a monocyte/
on both monocytes and macrophages.69 IL-13 up- macrophage deactivator in a manner similar to IL-
regulates cell surface expression of ␤2 integrins and 10. However, TGF-␤ is less potent an inhibitor than
major histocompatibility complex (MHC) class II IL-10 and has little or no effect on IL-1 produc-
antigens and down-regulates CD14 and Fc␥ recep- tion.81 The severe and uncontrolled inflammatory
tor expression. IL-13 inhibits NF-␬B activation in reactions observed in the TGF-␤1 knockout mouse
macrophages and protects against LPS-induced le- attests to the physiologic role of TGF-␤ as an
thality in animal models.73–75 endogenous anti-inflammatory cytokine.87
IL-13 suppresses lung inflammatory injury after
the deposition of IgG immune complexes.76 –78 Ex-
ogenous administration of anti-inflammatory cyto- Soluble Cytokine Receptors as
kines into the lungs of rats after IgG immune Anti-inflammatory Molecules
complex deposition reveals that the greatest inhibi-
tory activity is observed by IL-13 and IL-10, followed Both type 1 (p55) and type 2 (p75) receptors for
by IL-4 and IL-6. The potential role of IL-13 in human TNF-␣ may exist on the cell membrane as a
clinical medicine remains to be defined. signal-transducing unit or in a soluble form in the
extracellular fluid. The extracellular domain of both
TNF receptors may be solubilized into the systemic
TGF-␤
circulation, and they retain the capacity to bind
TGF-␤ is synthesized as an inactive precursor and TNF-␣ ligands at affinity levels that are comparable
requires activation before exerting its effect.79 The to those of membrane-bound TNF receptors.88 Sol-
active molecule is a 25-kd homodimer of two 12.5-kd uble receptors compete with membrane-bound re-
disulfide-linked monomers. It belongs to a super- ceptors for TNF binding. High amounts of soluble
family of ⬎ 20 distinct dimeric proteins that share a TNF receptors function as specific inhibitors of TNF
similar structure.80 There are three isoforms of activity on target tissues. Shedding of membrane-
TGF-␤ (designated TGF-␤1–3) expressed in mam- bound TNF receptors by susceptible target tissues
malian species. also tends to desensitize these tissues to TNF activ-
TGF-␤ is an important regulator of cell prolifera- ity.88 –90
tion, differentiation, and formulation of the extracel- It should be noted that TNF receptors may, under
lular matrix.81 In vitro, it inhibits growth of ectoder- certain circumstances, function as TNF agonists
mally derived cells.82 TGF-␤ induces squamous cell rather than TNF antagonists.91 This is known to
differentiation of human bronchial epithelial cells.83 occur specifically with soluble type 2 (p75) TNF
TGF-␤ has been shown to inhibit alveolar type II cell receptors. The soluble p75 TNF receptor may bind
proliferation and to decrease the expression of sur- to TNF-␣ in the circulation and prolong its circulat-
factant protein A in human lung explant cultures and ing half-life. Because TNF-␣ may readily dissociate
in a human lung adenocarcinoma cell line.84 TGF-␤ from the type 2 receptor, the end result may be
appears to contribute to the fibroproliferative phase prolongation of TNF activity in the systemic circu-
of acute lung injury from a variety of injurious lation with potentially detrimental effects.92 Both
agents.85 It plays a role in regulating the extracellular type 1 and type 2 receptors are readily measurable in
matrix by decreasing degradation of matrix proteins the circulation in humans under a variety of systemic
through a reduction in protease synthesis and an inflammatory and other pathologic states. The solu-
increase in the synthesis of protease inhibitors.86 ble receptor concentrations are sufficient to attenu-
Like many cytokines, TGF-␤ has both pro- and ate systemic TNF activity.93

CHEST / 117 / 4 / APRIL, 2000 1167

 Soluble IL-1 receptors are also measurable under Several bacterial pathogens have the capacity to
some pathologic states.13,14 The soluble receptor alter host cell cytokine synthesis, degrade proinflam-
found is primarily the type 2 receptor (p68) for IL-1. matory cytokines, or use cytokine receptors as portals
Soluble IL-1 receptors will bind to IL-1␣ and IL-1␤ of entry for cellular invasion.102 Pathogenic microor-
although they do not bind with high affinity to IL-1 ganisms have evolved a variety of ingenious mecha-
receptor antagonist.14 nisms to disrupt host defense mechanisms. Manipu-
The IL-1 type 2 receptor appears to function lation of the cytokine networks to the advantage of
primarily as a decoy receptor both in its soluble and the invading pathogen offers a further example of the
membrane-bound forms.15 The type 2 receptor has a importance of proinflammatory cytokines in the pro-
short transmembrane domain and intracellular do- tection against microbial invasion.
main and does not have the capacity to activate the Administration of inhibitors of proinflammatory
signal-transduction pathways. It appears to function cytokines (antibodies, soluble receptors, and anti-
as a molecular decoy that prevents interaction of inflammatory cytokines) in experimental models
IL-1␣ and IL-1␤ with the functional type 1 IL-1 generally provides an advantage in systemic toxicity
receptor.14 models such as endotoxin challenge studies.22,23
The recently described proinflammatory cytokine However, in localized infection models, inhibitors of
known as IL-18 also has a soluble receptor that the proinflammatory cytokine system may be detri-
functions to attenuate IL-18 activity.94 IL-18 is a mental to the host and precipitate overwhelming
macrophage product, which is initially synthesized as infection with excess mortality.7 This is particularly
pro-IL-18. The pro-peptide is cleaved into active true in the absence of appropriate antimicrobial
IL-18 through caspase-1. This is the same enzyme therapy against the invading microbial pathogen.7,46
that activates pro-IL-1␤ (IL-1␤ converting enzyme). The dichotomous nature of anti-inflammatory cyto-
Activated IL-18 stimulates the synthesis of IFN-␥ by kine responses in experimental systems is commonly
CD4⫹ T lymphocytes and has similar activities as observed in cytokine biology. Inadequate concentra-
the proinflammatory cytokine IL-12.95,96 tions of anti-inflammatory cytokines result in excess
A soluble receptor for IL-18 known as IL-18 inflammation, yet excess anti-inflammatory cytokine
binding protein has been measured in the serum and concentrations disrupt clearance mechanisms of mi-
urine of humans. The IL-18 binding protein lacks a crobial pathogens in the host.
transmembrane domain or intracellular domain and IL-10, soluble TNF receptors, and IL-1ra may be
circulates as the extracellular domain of IL-18 recep- found in high concentrations in the plasma of pa-
tor. It will bind to IL-18 in the systemic circulation tients with sepsis.2,54 Nonetheless, these anti-inflam-
and prevent IL-18 from binding to its membrane- matory agents must be present in far greater con-
bound receptor. The IL-18 receptor appears to be centrations than those of proinflammatory cytokines
closely related to the IL-1 receptor. The protein to inhibit their actions. Systemic concentrations of
formerly known as IL-1 receptor-related protein soluble cytokine inhibitors IL-1ra and IL-10 indicate
now appears to be the principal cell membrane that they are of sufficient magnitude to at least
receptor for IL-18 and is now referred to as IL-18 partially inhibit proinflammatory cytokine ac-
receptor.96 –98 tion.54,88,89,103 These results suggest that there may
well be a physiologic role for anti-inflammatory
Physiologic Role of Anti-inflammatory cytokines and soluble cytokine receptors in the face
Cytokines and Cytokine Inhibitors of systemic inflammation.
Recent evidence indicates that individuals differ in
A complex network of cytokines is generated in their susceptibility to systemic infection and inflam-
response to a systemic immune challenge. It is the matory states on the basis of their cytokine profiles
net effect of interactions between these proinflam- and genetic background. Patients and first-degree
matory and anti-inflammatory molecules over time relatives of patients with meningococcemia are more
that determines the nature of the immune response likely to have fatal infections if they have high ratios
in individual patients.1,4,8,11 Microbial pathogens may of IL-10 to TNF-␣.5 Similarly, patients with high
actually use components of the cytokine network to ratios of TNF to soluble TNF receptors are at
their own advantage. A number of DNA viruses increased risk of having lethal meningococcal infec-
synthesize soluble TNF receptor and IL-1 recep- tions.104
tors.99,100 Epstein-Barr virus mediates the synthesis Allelic polymorphism within the second intron of
of viral IL-10 in infected human B cells.101 These the IL-1ra gene indicates that individuals who have
viral-induced anticytokine strategies appear to assist the IL-1ra A2 allele have a greater propensity to
the virus in the promotion of viral replication and develop severe sepsis than do patients with other
evasion of host-derived clearance mechanisms. IL-1ra alleles.21 A polymorphism in a regulatory

1168 Impact of Basic Research on Tomorrow’s Medicine

region of the human TNF-␤ gene is associated with lung fields of patients with the adult respiratory distress
excess risk of death caused by sepsis (the TNF B2 syndrome. Ann Intern Med 1996; 125:191–196
7 Opal SM, Cross AS, Jhung J, et al. Potential hazards of
homozygous genotype).105 Mira and colleagues106
combination immunotherapy in the treatment of experimen-
have recently described differences in septic shock tal sepsis. J Infect Dis 1996; 173:1415–1421
susceptibility and mortality associated with a poly- 8 van de Poll T, Marchant A, van Deventer SJH. The role of
morphism at the TNF-␣ promotor site in human interleukin-10 in the pathogenesis of bacterial infection.
populations. Individuals born with mutations in the Clin Microbiol Infect 1997; 3:605– 607
genes for the IFN-␥ receptor107 or IL-12 receptor108 9 Mosmann TR, Cherwinski H, Bond MW, et al. Two types of
murine helper T-cell clone: I. Definition according to
are highly susceptible to lethal infections caused by profiles of lymphokine activities and secreted proteins.
mycobacterial infection. These studies make it clear J Immunol 1986; 136:2348 –2357
that alterations in cytokine networks can have a 10 Kelso A. Th1 and Th2 subsets: paradigms lost? Immunol
significant impact on the human host response to a Today 1995; 16:374 –379
variety of infectious agents and inflammatory states. 11 Zedler S, Bone RC, Baue AE, et al. T-cell reactivity and its
predictive role in immunosuppression after burns. Crit Care
Despite complexities inherent in the human im- Med 1999; 27:66 –72
mune response, therapeutic intervention with spe- 12 Dinarello CA. Biologic basis for interleukin-1 in disease.
cific cytokine inhibitors or anti-inflammatory cyto- Blood 1996; 87:2095–2147
kines has already been shown to have significant 13 Opal SM. Interleukin-1 receptor antagonist in sepsis. In:
clinical benefits.65,109 Several of these agents are Bodmer M, Henderson W, eds. Therapeutic modulation of
the cytokines. London, UK: CRC Press, 1996; 196 –219
already approved for clinical use, and others are 14 Dinarello CA. Induction of interleukin-1 and interleukin-1
undergoing extensive clinical trials for a variety of receptor antagonist. Semin Oncol 1997; 24(suppl):S9 – 81,
inflammatory disease states (Table 3). S9 –93
It is fully anticipated that carefully performed 15 Simms JE, Gayle MA, Slack JL, et al. Interleukin-1 signaling
clinical studies in selected patient populations will occurs exclusively via type 1 receptor. Proc Natl Acad Sci
USA 1993; 90:6155– 6159
demonstrate efficacy of these immunomodulatory 16 Greenfeder SA, Nunes P, Kwee L, et al. Molecular cloning
agents in human disease. The ability to rapidly assess and characterization of a second subunit of the interleukin-1
the state of the human immune response and regu- receptor complex. J Biol Chem 1995; 270:13757–13765
late this response in the presence of a variety of 17 Schreuder H, Tardif C, Trump-Kallmeyer S, et al. A new
human disease states has been the goal of immunol- cytokine-receptor binding mode revealed by the crystal
structure of the IL-1 receptor with an antagonist. Nature
ogists for the past century. Advances in human 1997; 386:194 –200
genetics and immunobiology now provide an oppor- 18 Danis VA, Millington M, Hyland VJ, et al. Cytokine produc-
tunity to capitalize on recent discoveries in basic tion by normal human monocytes: inter-subject variation
immunology and cytokine biology. It should soon be and relationship to an interleukin-1 receptor antagonist
possible to intelligently use these immunoregulatory (IL-1ra) gene polymorphism. Clin Exp Immunol 1995;
99:303–310
cytokines to the benefit of our patients. It is likely 19 Miller LC, Lynch EA, Isa S, et al. Balance of synovial fluid,
that anti-inflammatory cytokines and specific cyto- IL-1 ␤ and IL-1 receptor antagonist in recovery from Lyme
kine inhibitors will increasingly find their way into arthritis. Lancet 1993; 341:146 –147
standard clinical practice as we enter the next mil- 20 Wilkinson RJ, Patel P, Llewelyn M, et al. Influence of
lennium. polymorphism in the genes of interleukin-1 receptor antag-
onist and IL-1␤ on tuberculosis. J Exp Med 1999; 189:1863–
1873
21 Fang XM, Schröder S, Hoeft A, et al. Comparison of two
References polymorphisms of the interleukin-1 gene family: interleu-
1 Munoz C, Carlet J, Fitting C, et al. Dysregulation of in vitro kin-1 receptor antagonist polymorphism contributes to sus-
cytokine production by monocytes during sepsis. J Clin ceptibility to severe sepsis. Crit Care Med 1999; 27:1330 –
Invest 1991; 88:1747–1754 1334
2 Kasai T, Inada K, Takakuwa T, et al. Anti-inflammatory 22 Russel DA, Tucker KK, Khinookoswong N, et al. Combined
cytokine levels in patients with septic shock. Res Commun inhibition of interleukin-1 in tumor necrosis factor in rodent
Mol Pathol Pharmacol 1997; 98:34 – 42 endotoxemia: improved survival and organ function. J Infect
3 Dinarello CA. Interleukin-1, interleukin-1 receptors and Dis 1995; 171:1528 –1538
interleukin-1 receptor antagonist. Int Rev Immunol 1998; 23 Aiura K, Gelfand JA, Burke JF, et al. Interleukin-1 (IL-1)
16:457– 499 receptor antagonist prevents Staphylococcus epidermidis-
4 Döcke WD, Randow F, Syrbe U, et al. Monocyte deactiva- induced hypotension and reduces circulating levels of tumor
tion in septic patients: restoration by interferon gamma necrosis factor and IL-1 beta in rabbits. Infect Immun 1993;
treatment. Nat Med 1997; 3:678 – 681 61:3342–3350
5 Westendorp RGJ, Langermans JAM, Huizinga TWJ, et al. 24 Opal SM, Fisher CF, Dhainaut J-F, et al. Confirmatory
Genetic influence on cytokine production in fatal meningo- interleukin-1 receptor antagonist trial in severe sepsis: a
coccal disease. Lancet 1997; 349:170 –173 phase III randomized, double-blind, placebo-controlled
6 Donnelly SC, Strieter RM, Reid PT, et al. The association multicenter trial. Crit Care Med 1997; 25:1115–1124
between mortality rates and decreased concentrations of 25 Bresnihan B, Alvaro-Gracia JM, Cobby M, et al. Treatment
interleukin-10 and interleukin-1 receptor antagonist in the of rheumatoid arthritis with recombinant human interleu-

CHEST / 117 / 4 / APRIL, 2000 1169

 kin-1 receptor antagonist. Arthritis Rheum 1998; 41:2196 – 45 Howard M, O’Garra A. Biological properties of interleukin-
2204 10. Immunol Today 1992; 13:198 –200
26 Brown MA, Hural J. Functions of IL-4 and control of its 46 Opal SM, Wherry JC, Grint P. Interleukin-10: potential
expression. Crit Rev Immunol 1997; 17:1–32 benefits and possible risks in clinical infectious diseases. Clin
27 Wang P, Wu P, Siegel ML, et al. Interleukin (IL)-10 inhibits Infect Dis 1998; 27:1497–1507
nuclear factor ␬B (NF-␬B) activation in human monocytes: 47 Brandtzaeg P, Osnes L, Ovstebo R, et al. Net inflammatory
IL-10 and IL-4 suppress cytokine synthesis by different capacity of human septic shock plasma evaluated by a
mechanisms. J Biol Chem 1995:9558 –9563 monocyte-based target cell assay: identification of interleu-
28 te Velde AA, Huijbens RJF, de Vries JE, et al. Interleukin-4 kin-10 as a major functional deactivator of human mono-
(IL-4) inhibits secretion of IL-1␤, tumor necrosis factor ␣, cytes. J Exp Med 1996; 184:51– 60
and human IL-6 by human monocytes. Blood 1990; 76: 48 Clarke CJP, Hales A, Hunt A, et al. IL-10 mediated
1392–1397 suppression of TNF-␣ production is independent of its
29 Paul WE. Interleukin-4: a prototypic immunoregulatory ability to inhibit NF-␬B activity. Eur J Immunol 1998;
lymphokine. Blood 1991; 77:1859 –1870 28:1719 –1726
30 Vannier E, Miller MC, Dinarello CA. Coordinated anti- 49 Gérard D, Bryns C, Marchant A, et al. Interleukin 10
inflammatory effects of interleukin4: interleukin 4 sup- reduces the release of tumor necrosis factor and prevents
presses interleukin 1 production but up-regulates gene lethality in experimental endotoxemia. J Exp Med 1993;
expression and synthesis of interleukin 1 receptor antago- 177:547–550
nist. Proc Natl Acad Sci USA 1992; 89:4076 – 4080 50 Marchant A, Bruyns C, Vandenabeele P, et al. Interleu-
31 Hart PH, Vitti GF, Burgess DR, et al. Potential anti- kin-10 controls interferon-␥ and tumor necrosis factor pro-
inflammatory effects of interleukin 4: suppression of human duction during experimental endotoxemia. Eur J Immunol
monocyte tumor necrosis factor alpha, interleukin 1, and 1994; 24:1167–1171
prostaglandin E2. Proc Natl Acad Sci USA 1989; 86:3803– 51 Dickensheets HL, Freeman SL, Smith MF, et al. Interleu-
3807 kin-10 upregulates tumor necrosis factor receptor type II
32 Jain-Vora S, LeVine AM, Chroneos Z, et al. Interleukin-4 (p75) gene expression in endotoxin-stimulated human
enhances pulmonary clearance of Pseudomonas aeruginosa. monocytes. Blood 1997; 90:4162– 4171
Infect Immun 1998; 66:4229 – 4236 52 Joyce DA, Gibbons DP, Geen P, et al. Two inhibitors of
33 Hultgren O, Kopf M, Tarkowski A. Staphylococcus aureus- pro-inflammatory cytokine release, interleukin-10 and inter-
induced septic arthritis and septic death is decreased in leukin-4, have contrasting effects on release of soluble p75
IL-4-deficient mice: role of IL-4 as promoter for bacterial tumor necrosis factor receptor by cultured monocytes. Eur
growth. J Immunol 1998; 160:5082–5087 J Immunol 1994; 24:2699 –2705
34 Toi M, Harris AL, Bicknell R. Interleukin-4 is a potent 53 Marchant A, Deviere J, Byl B, et al. Interleukin-10 produc-
mitogen for capillary endothelium. Biochem Biophys Res tion during septicaemia. Lancet 1994; 343:707–708
Commun 1991; 174:1287–1293 54 van der Poll T, de Waal Malefyt R, Coyle SM, et al.
35 Tepper RI, Coffman RL, Leder P. An eosinophil-dependent Anti-inflammatory cytokine responses during clinical sepsis
mechanism of the antitumor effect of IL-4. Science 1992; and experimental endotoxemia: sequential measurements of
257:548 –551 plasma soluble interleukin (IL)-1 receptor type II, IL-10,
36 Toi M, Bicknell R, Harris AL. Inhibition of colon and breast and IL-13. J Infect Dis 1997; 175:118 –122
carcinoma cell growth by interleukin-4. Cancer Res 1992; 55 Lehmann AK, Halstensen A, Sornes S, et al. High levels of
52:275–279 interleukin-10 in serum are associated with fatality in me-
37 Vokes EE, Figlin R, Hochster H, et al. A phase II study of ningococcal disease. Infect Immun 1995; 63:2109 –2112
recombinant human interleukin-4 for advanced or recurrent 56 Westendorp RGJ, Langermans JAM, Hurizinga TWJ, et al.
non-small cell lung cancer. Cancer J Sci Am 1998; 4:46 –51 Genetic influence on cytokine production in fatal meningo-
38 Barton BE. IL-6: insights into novel biological activities. coccal disease. Lancet 1997; 349:170 –173
Clin Immunol Immunopathol 1997; 85:16 –20 57 van Dissel JT, van Langevelde P, Westendorp RGJ, et al.
39 Barton BE, Shortall J, Jackson JV. Interleukins 6 and 11 Anti-inflammatory cytokine profile and mortality in febrile
protect mice from mortality in a staphylococcal enterotoxin- patients. Lancet 1998; 351:950 –953
induced toxic shock model. Infect Immun 1996; 64:714 –718 58 Pajkart D, Camoglio L, Tiel-van Buul MCM, et al. Attenu-
40 Libert C, Takahashi N, Cauwels A, et al. Response of ation of pro-inflammatory response by recombinant human
interleukin-6-deficient mice to tumor necrosis factor-in- IL-10 in human endotoxemia: the effect of timing of rhIL-10
duced metabolic changes and lethality. Eur J Immunol 1994; administration. J Immunol 1997; 158:3971–3977
24:2237–2242 59 Dai W, Kohler G, Brombacher F. Both innate and acquired
41 Xing Z, Gauldie J, Cox G, et al. IL-6 is an anti-inflammatory immunity to Listeria monocytogenes infections are increased
cytokine required for controlling local or systemic acute in IL-10-deficient mice. J Immunol 1997; 158:2259 –2267
inflammatory responses. J Clin Invest 1998; 101:311–320 60 van der Poll T, Marchant A, Koeogh CF, et al. Interleu-
42 Ruzek MC, Miller AH, Opal SM, et al. Characterization of kin-10 impairs host defense in murine pneumococcal pneu-
early cytokine responses in an interleukin-6-dependent monia. J Infect Dis 1996; 174:994 –1000
pathway of endogenous glucocorticoid induction during 61 Greenberger MJ, Strieter RM, Kunkel SL, et al. Neutraliza-
murine cytomegalovirus infection. J Exp Med 1997; 185: tion of IL-10 increases survival in a murine model of
1185–1192 Klebsiella pneumonia. J Immunol 1995; 155:722–729
43 Tilg H, Trehu E, Atkins MB, et al. Interleukin-6 as an 62 Kühn R, Löhler J, Rennick D, et al. Interleukin-10-deficient
anti-inflammatory cytokine: induction of circulating IL-1 mice develop chronic enterocolitis. Cell 1993; 75:263–274
receptor antagonist and soluble tumor necrosis factor recep- 63 Du XX, Williams DA. Interleukin-11: a multifunctional
tor p55. Blood 1994; 83:113–118 growth factor derived from the hematopoietic micro-envi-
44 Lalani I, Bhoi K, Ahmed AF. Interleukin-10: biology, role in ronment. Blood 1994; 83:2023–2030
inflammation and autoimmunity. Ann Allergy 1997; 79:469 – 64 Neddermann P, Graiziani R, Ciliberto G, et al. Functional
483 expression of soluble interleukin-11 (IL-11) receptor ␣ and

1170 Impact of Basic Research on Tomorrow’s Medicine

 stoichiometry of in vitro IL-11 receptor complexes with lung cancer cell lines is associated to expression of the type
GP130. J Biol Chem 1996; 271:30986 –30991 II receptor. Br J Cancer 1994; 69:802– 808
65 Tepler I, Elias L, Smith JW, et al. A randomized-placebo- 84 Jetten AM, Shirley JE, Stoner G. Regulation and prolifera-
controlled trial of recombinant human interleukin-11 in tion and differentiation of respiratory tract epithelial cells by
cancer patients with severe thrombocytopenia due to che- TGF-␤. Exp Cell Res 1986; 167:539 –549
motherapy. Blood 1996; 87:3607–3614 85 Santana A, Saxena B, Noble NA, et al. Increased expression
66 Trepicchio WL, Wang L, Bozza N, et al. Interleukin-11 of transforming growth factor ␤ isoforms (␤1, ␤2, ␤3) in
regulates macrophage effector function through the inhibi- bleomycin-induced pulmonary fibrosis. Am J Respir Cell
tion of nuclear factor-␬B. J Immunol 1997; 159:5661–5669 Mol Biol 1995; 13:34 – 44
67 Hill GR, Cooke KR, Teshima T, et al. Interleukin-11 86 Roberts AB, Flanders KC, Kondaiah P, et al. Transforming
promotes T cell polarization and prevents acute graft-vs-host growth factor-␤ biochemistry and roles in embryogenesis,
disease after allogeneic bone marrow transplantation. J Clin tissue repair and remodeling, and carcinogenesis. Recent
Invest 1998; 201:115–123 Prog Horm Res 1988; 44:157–197
68 Hermann JA, Hall MA, Maini RN, et al. Important immu- 87 Shull MM, Ormsby I, Kier AB, et al. Targeted disruption of
noregulatory role of interleukin-11 in the inflammatory the mouse transforming growth factor-␤1 gene results in
process in rheumatoid arthritis. Arthritis Rheum 1998; multifocal inflammatory disease. Nature 1992; 359:693– 699
41:1388 –1397 88 van der Poll T, Jansen J, van Leenen D, et al. Release of
69 de Waal Malefyt R, Figdor CG, Huijbens R, et al. Effects of soluble receptors for tumor necrosis factor in clinical sepsis
IL-13 on phenotype, cytokine production, and cytotoxic and experimental endotoxemia. J Infect Dis 1993; 168:955–
function of human monocytes. J Immunol 1993; 151:6370 – 960
6381 89 Ertel W, Scholl FA, Galatti H, et al. Increased release of
70 Zurawski G, de Vries JE. Interleukin 13, an interleukin-4- soluble tumor necrosis factor receptors into blood during
like cytokine that acts on monocytes and B cells, but not on clinical sepsis. Arch Surg 1994; 129:1330 –1337
T cells. Immunol Today 1994; 15:19 –26 90 van Deuren M, Frieling TM, van der ven-Jongekrijg J, et al.
71 McKenzie AN, Li X, Largaespada DA, et al. Structural Plasma patterns of tumor necrosis factor-␣ and TNF soluble
comparison and chromosomal localization of the human and receptors during acute meningococcal infections and the
mouse IL-13 genes. J Immunol 1993; 150:5436 –5444 effect of plasma exchange. Clin Infect Dis 1998; 26:918 –923
72 Callard RE, Matthews DJ, Hibbert L. IL-4 and IL-13 91 Mohler KM, Torrance DS, Smith CA, et al. Soluble tumor
receptors: are they one and the same? Immunol Today 1996; necrosis factor (TNF) receptors are effective therapeutic
17:108 –110 agents in lethal endotoxemia and function simultaneously as
73 Mijatovic T, Kruys V, Caput D, et al. Interleukin-4 and -13 both TNF carriers and TNF antagonists. J Immunol 1993;
inhibit tumor necrosis factor-␣ mRNA translational activa- 151:1548 –1561
tion in lipopolysaccharide-induced mouse macrophages. 92 Evans TJ, Moyes D, Carpenter A, et al. Protective effect of
J Biol Chem 1997; 272:14394 –14398 55- but not 75-kD soluble tumor necrosis factor receptor-
74 Di Santo E, Meazza C, Sironi M, et al. IL-13 inhibits TNF immunoglobulin G fusion proteins in an animals model of
production but potentiates that of IL-6 in vivo and ex vivo in Gram-negative sepsis. J Exp Med 1994; 180:2173–2179
mice. J Immunol 1997; 159:379 –382 93 Van Zee KJ, Kohno T, Fisher E, et al. Tumor necrosis factor
75 Muchamuel T, Menon S, Pisacane P, et al. IL-13 protects soluble receptors circulate during experimental and clinical
mice from lipopolysaccharide-induced lethal endotoxemia: inflammation and can protect against excessive tumor ne-
correlation with down-modulation of TNF-␣, IFN-␥, and crosis factor␣ in vitro and in vivo. Proc Natl Acad Sci USA
IL-12 production. J Immunol 1997; 158:2898 –2903 1992; 89:4845– 4849
76 Mulligan MS, Warner RL, Foreback JL, et al. Protective 94 Aizawa Y, Akita K, Taniai M, et al. Cloning and expression of
effects of IL- 4, IL-10, IL-12, and IL-13 in IgG immune interleukin-18 binding protein. FEBS Lett 1999; 445:338 –
complex-induced lung injury: role of endogenous IL-12. 342
J Immunol 1997; 159:3483–3489 95 Yoshimoto T, Takeda K, Tanaka T, et al. IL-12 up-regulates
77 Lentsch AB, Czermak BJ, Bless NM, et al. NF-␬B activation IL-18 receptor expression on T cells, Th1 cells, and B cells:
during IgG immune complex-induced lung injury: require- synergism with IL-18 for IFN-␥ production. J Immunol
ments for TNF-␣ and IL-1␤ but not complement. Am J 1998; 161:3400 –3407
Pathol 1998; 152:1327–1336 96 Thomassen E, Bird TA, Renshaw BR, et al. Binding of
78 Lentsch AB, Czermak BJ, Jordan JA, et al. Regulation of interleukin-18 to the interleukin-1 receptor homologous
acute lung inflammatory injury by endogenous IL-13. J Im- receptor IL-1Rrpl leads to activation of signaling pathways
munol 1999; 162:1071–1076 similar to those used by interleukin-1. J Interferon Cytokine
79 Norgaard P, Hougaard S, Spang-Thomsen M, et al. Trans- Res 1998; 18:1077–1088
forming growth factor ␤ and cancer. Cancer Treat Rev 1995; 97 Hoshino K, Tsutsui H, Kawai T, et al. Cutting edge:
21:367– 403 generation of IL-18 receptor-deficient mice; evidence for
80 Kingsley DM. The TGF-␤superfamily: new members, new IL-1 receptor-related protein as an essential IL-18 binding
receptors and new genetic tests of function in different receptor. J Immunol 1999; 62:5041–5044
organisms. Genes Dev 1994; 8:133–146 98 Kanakaraj P, Ngo K, Wu Y, et al. Defective interleukin
81 Litterio JJ, Roberts AB. TGF-␤: a critical modulator of (IL)-18-mediated natural killer and T helper cell type 1
immune cell function. Clin Immunol Immunopathol 1997; responses in IL-1 receptor-associated kinase (IRAK)-defi-
84:244 –250 cient mice. J Exp Med 1999; 189:1129 –1138
82 Roberts AB, Sporn MB. Differential expression of the 99 Spriggs MK. One step ahead of the game: viral immuno-
TGF-␤ isoforms in embryogenesis suggests specific roles in modulatory molecules. Annu Rev Immunol 1996; 14:101–
developing and adult tissues. Mol Reprod Dev 1992; 32: 130
91–98 100 Ploegh HL. Viral strategies of immune evasion. Science
83 Norgaard P, Damstrup L, Rygaard K, et al. Growth suppres- 1998; 280:248 –253
sion by transforming growth factor-␤1 of human small cell 101 Moore KW, Vieira P, Fiorentino DF, et al. Homology of

CHEST / 117 / 4 / APRIL, 2000 1171

 cytokine synthesis inhibitory factor (IL-10) to Epstein-Barr 106 Mira J-P, Cariou A, Grall F, et al. Association of TNF2, a
virus gene BCRF1. Science 1990; 248:1230 –1234 TNF-␣ promotor polymorphism, with septic shock suscep-
102 Wilson M, Seymour R, Henderson B. Bacterial perturbation tibility and mortality: a multicenter study. JAMA 1999;
of cytokine networks. Infect Immun 1998; 66:2401–2409 282:561–568
103 Goldie AS, Fearon KCHM, Ross JA, et al. Natural cytokine 107 Dorman SE, Holland SM. Mutation in the signal-transduc-
antagonists and endogenous anti-endotoxin core antibodies ing chain of the interferon gamma receptor has susceptibility
in sepsis syndrome. JAMA 1995; 274:172–177 to mycobacterial infection. J Clin Invest 1998; 101:2364 –
104 Girardin E, Roux-Lomberd P, Grau GE, et al. Imbalance be- 2369
tween tumor necrosis factor-␣ and soluble TNF receptor concen- 108 Jong R, Altare F, Haagen IA, et al. Severe mycobacterial and
tration in severe meningococcaemia. Immunology 1992; 76:20–23 salmonella infections in interleukin-12 receptor-deficient
105 Stüber F, Petersen M, Bokelmann F, et al. A genomic patients. Science 1998; 280:1435–1438
polymorphism within the tumor necrosis factor locus influ- 109 Moreland LW, Baumgartner SW, Schiff MH, et al. Treat-
ences plasma tumor necrosis factor-␣ concentrations and ment of rheumatoid arthritis with a recombinant human
outcome of patients with severe sepsis. Crit Care Med 1996; tumor necrosis factor receptor (p75)-Fc fusion protein.
24:381–384 N Engl J Med 1997; 337:141–147

1172 Impact of Basic Research on Tomorrow’s Medicine