Chest
Volume 117, Issue 4, April 2000, Pages 1162-1172
Journal home page for Chest

Impact of Basic Research on Tomorrow's Medicine
Anti-Inflammatory Cytokines

https://doi.org/10.1378/chest.117.4.1162Get rights and content

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-α, 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.

Section snippets

IL-1ra

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-1α and IL-1β.3, 12 The human gene for IL-1ra is on the long arm of chromosome 2 in close proximity to the genes for IL-1α and IL-1β. Genetic evidence indicates that IL-1ra diverged from an ancestral IL-1 gene as a partial duplication event early in vertebrate evolution.12, 13 IL-1ra shares approximately 26% amino acid sequence homology with IL-1β and 19% homology

Soluble Cytokine Receptors as Anti-inflammatory Molecules

Both type 1 (p55) and type 2 (p75) receptors for human TNF-α may exist on the cell membrane as a 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 circulation, and they retain the capacity to bind TNF-α ligands at affinity levels that are comparable to those of membrane-bound TNF receptors.88 Soluble receptors compete with membrane-bound receptors for TNF binding. High amounts of soluble

Physiologic Role of Anti-inflammatory Cytokines and Cytokine Inhibitors

A complex network of cytokines is generated in response to a systemic immune challenge. It is the net effect of interactions between these proinflammatory and anti-inflammatory molecules over time that determines the nature of the immune response in individual patients.1, 48, 11 Microbial pathogens may actually use components of the cytokine network to their own advantage. A number of DNA viruses synthesize soluble TNF receptor and IL-1 receptors.99, 100 Epstein-Barr virus mediates the

References (109)

  • M Howard et al.

    Biological properties of interleukin-10

    Immunol Today

    (1992)
  • HL Dickensheets et al.

    Interleukin-10 upregulates tumor necrosis factor receptor type II (p75) gene expression in endotoxin-stimulated human monocytes

    Blood

    (1997)
  • A Marchant et al.

    Interleukin-10 production during septicaemia

    Lancet

    (1994)
  • RGJ Westendorp et al.

    Genetic influence on cytokine production in fatal meningococcal disease

    Lancet

    (1997)
  • JT van Dissel et al.

    Anti-inflammatory cytokine profile and mortality in febrile patients

    Lancet

    (1998)
  • R Ku¨hn et al.

    Interleukin-10-deficient mice develop chronic enterocolitis

    Cell

    (1993)
  • XX Du et al.

    Interleukin-11: a multifunctional growth factor derived from the hematopoietic micro-environment

    Blood

    (1994)
  • P Neddermann et al.

    Functional expression of soluble interleukin-11 (IL-11) receptor α and stoichiometry of in vitro IL-11 receptor complexes with GP130

    J Biol Chem

    (1996)
  • I Tepler et al.

    A randomized-placebo-controlled trial of recombinant human interleukin-11 in cancer patients with severe thrombocytopenia due to chemotherapy

    Blood

    (1996)
  • G Zurawski et al.

    Interleukin 13, an interleukin-4-like cytokine that acts on monocytes and B cells, but not on T cells

    Immunol Today

    (1994)
  • RE Callard et al.

    IL-4 and IL-13 receptors: are they one and the same?

    Immunol Today

    (1996)
  • T Mijatovic et al.

    Interleukin-4 and -13 inhibit tumor necrosis factor-α mRNA translational activation in lipopolysaccharide-induced mouse macrophages

    J Biol Chem

    (1997)
  • P Norgaard et al.

    Transforming growth factor β and cancer

    Cancer Treat Rev

    (1995)
  • AM Jetten et al.

    Regulation and proliferation and differentiation of respiratory tract epithelial cells by TGF-β

    Exp Cell Res

    (1986)
  • AB Roberts et al.

    Transforming growth factor-β biochemistry and roles in embryogenesis, tissue repair and remodeling, and carcinogenesis

    Recent Prog Horm Res

    (1988)
  • Y Aizawa et al.

    Cloning and expression of interleukin-18 binding protein

    FEBS Lett

    (1999)
  • C Munoz et al.

    Dysregulation of in vitro cytokine production by monocytes during sepsis

    J Clin Invest

    (1991)
  • T Kasai et al.

    Anti-inflammatory cytokine levels in patients with septic shock

    Res Commun Mol Pathol Pharmacol

    (1997)
  • CA Dinarello

    Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist

    Int Rev Immunol

    (1998)
  • WD Do¨cke et al.

    Monocyte deactivation in septic patients: restoration by interferon gamma treatment

    Nat Med

    (1997)
  • SC Donnelly et al.

    The association between mortality rates and decreased concentrations of interleukin-10 and interleukin-1 receptor antagonist in the lung fields of patients with the adult respiratory distress syndrome

    Ann Intern Med

    (1996)
  • SM Opal et al.

    Potential hazards of combination immunotherapy in the treatment of experimental sepsis

    J Infect Dis

    (1996)
  • T van de Poll et al.

    The role of interleukin-10 in the pathogenesis of bacterial infection

    Clin Microbiol Infect

    (1997)
  • TR Mosmann et al.

    Two types of murine helper T-cell clone: I. Definition according to profiles of lymphokine activities and secreted proteins

    J Immunol

    (1986)
  • S Zedler et al.

    T-cell reactivity and its predictive role in immunosuppression after burns

    Crit Care Med

    (1999)
  • SM Opal

    Interleukin-1 receptor antagonist in sepsis

  • CA Dinarello

    Induction of interleukin-1 and interleukin-1 receptor antagonist

    Semin Oncol

    (1997)
  • JE Simms et al.

    Interleukin-1 signaling occurs exclusively via type 1 receptor

    Proc Natl Acad Sci USA

    (1993)
  • H Schreuder et al.

    A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist

    Nature

    (1997)
  • VA Danis et al.

    Cytokine production by normal human monocytes: inter-subject variation and relationship to an interleukin-1 receptor antagonist (IL-1ra) gene polymorphism

    Clin Exp Immunol

    (1995)
  • LC Miller et al.

    Balance of synovial fluid, IL-1 β and IL-1 receptor antagonist in recovery from Lyme arthritis

    Lancet

    (1993)
  • RJ Wilkinson et al.

    Influence of polymorphism in the genes of interleukin-1 receptor antagonist and IL-1β on tuberculosis

    J Exp Med

    (1999)
  • XM Fang et al.

    Comparison of two polymorphisms of the interleukin-1 gene family: interleukin-1 receptor antagonist polymorphism contributes to susceptibility to severe sepsis

    Crit Care Med

    (1999)
  • DA Russel et al.

    Combined inhibition of interleukin-1 in tumor necrosis factor in rodent endotoxemia: improved survival and organ function

    J Infect Dis

    (1995)
  • K Aiura et al.

    Interleukin-1 (IL-1) receptor antagonist prevents Staphylococcus epidermidis -induced hypotension and reduces circulating levels of tumor necrosis factor and IL-1 beta in rabbits

    Infect Immun

    (1993)
  • SM Opal et al.

    Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III randomized, double-blind, placebo-controlled multicenter trial

    Crit Care Med

    (1997)
  • B Bresnihan et al.

    Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist

    Arthritis Rheum

    (1998)
  • MA Brown et al.

    Functions of IL-4 and control of its expression

    Crit Rev Immunol

    (1997)
  • E Vannier et al.

    Coordinated anti-inflammatory effects of interleukin4: interleukin 4 suppresses interleukin 1 production but up-regulates gene expression and synthesis of interleukin 1 receptor antagonist

    Proc Natl Acad Sci USA

    (1992)
  • PH Hart et al.

    Potential anti-inflammatory effects of interleukin 4: suppression of human monocyte tumor necrosis factor alpha, interleukin 1, and prostaglandin E2

    Proc Natl Acad Sci USA

    (1989)
  • Cited by (1278)

    View all citing articles on Scopus
    View full text