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Anti-Inflammatory Cytokines*
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-a, and IL-18 also function as proinflammatory cytokine inhibitors. The nature of anti-inflammatory cytokines and soluble cytolane 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-macrophaga colony-stimulating factor; IFN-gamma = interferon-gamma; IL = interleuldn; IL-1ra = IL-1 receptor antagonist; LPS = Lipopolysaccharide; MHC = major histocompatibility complex; MIP = macrophage inflammatory protein; NF-KappaB = nuclear factor KB; TGF-beta = transforming growth factor-beta; Th = T helper cells; TNF = tumor necrosis factor
The human immune response is regulated by a highly complex and intricate network of control elements. Prominent among these regulatory components are the anti-inflammatory cytokines and specific cytokine inhibitors. Under physiologic conditions, these cytokine inhibitors serve as immunomodulatory elements that limit the potentially injurious effects of sustained or excess inflammatory reactions. Under pathologic conditions, these antiinflammatory mediators may either (1) provide insufficient 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 between proinflammatory cytokines and anti-inflammatory 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 receptor density, and tissue responsiveness to each cytokine.3 This is what makes the study of cytokine biology so fascinating...