Anti-Inflammatory Interleukins

Anti-inflammatory interleukins, are cytokines that play great roles in counterbalancing the pro-inflammatory response in various infectious diseases. Major anti-inflammatory interleukins include interleukin (IL)-1 receptor antagonist, IL-4, IL-6, IL-10, IL-13, IL-19 and IL-35.

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Anti-Inflammatory Interleukins Function

Interleukin-1 receptor antagonist (IL-1Ra), possesses anti-inflammatory effects. IL-1Ra is a naturally occurring cytokine and is the inhibitor of IL-1. When IL-1Ra binds to the IL-1 receptor, binding of IL-1 is blocked by IL-1Ra and pro-inflammatory signal from IL-1 receptor is stopped. There are mounting evidences to suggest that anti-inflammatory IL-1Ra reduces the inflammatory effects of IL-1 and preserves cell function in both types of diabetes.

IL-4, an anti-inflammatory interleukin, is able to directs a programme of alternative macrophage activation. In contrast to classically activated (M1) macrophages, which participate in a T helper type 1 (Th1) polarized response and enhance production of pro-inflammatory cytokines, alternatively activated (M2) macrophages counteract inflammation via the release of IL-1ra, IL-10 and transforming growth factor (TGF)-β and promote wound healing and tissue repair.

IL-6, is a cytokine not only involved in inflammation and infection responses but also in the regulation of metabolic, regenerative, and neural processes. IL-6 is a interleukin which possesses pro- and anti-inflammatory properties. It turns out that regenerative or anti-inflammatory activities of interleukin-6 are mediated by classic signaling whereas pro-inflammatory responses of interleukin-6 are rather mediated by trans-signaling. This is important since therapeutic blockade of interleukin-6 by the neutralizing anti-interleukin-6 receptor monoclonal antibody tocilizumab has recently been approved for the treatment of inflammatory diseases.

IL-10, an anti-inflammatory interleukin, is secreted under different conditions of immune activation by a variety of cell types, including T cells, B cells, and monocytes/macrophages. Although IL-10 is classified as a Th2-type cytokine, it has been shown to suppress a broad range of inflammatory responses and is known to be an important factor in maintaining homeostasis of overall immune responses. Thus, novel therapies using IL-10 have been developed for several human diseases such as allergic responses and autoimmune. Little is known about the anti-inflammatory effect of IL-10 during a C. trachomatis infection.

Anti-inflammatory cytokine IL-13 can inhibit the synthesis of pro-inflammatory cytokines by activated monocytes/macrophages. IL-13 inhibits chemokine synthesis by vascular endothelial and airway smooth-muscle cells, although it can enhance chemokine synthesis in some systems. In vivo, IL-13 has been shown to inhibit TNF-α release, neutrophil accumulation, and TNF-α production in rat lung immune complex injury, and endotoxin-induced lethality and increased serum TNF-α in the mouse.

Like IL-10, IL-19 is a Th2 anti-inflammatory interleukin. Interleukin-19 (IL-19) is an IL-10 family member expressed in monocytes, T, and B lymphocytes, and can be up regulated in these cells by LPS and G-CSF. Treatment of maturing antigen-presenting cells with IL-19 promotes of the Th2 (regulatory), rather than the Th1 (T helper) response, and induces IL-10, and decreases IFNγ expression in T cells. The notion that a Th2 anti-inflammatory interleukin can directly regulate EC pathophysiology is novel, and has important implications for the role of anti-inflammatory mediators in vasculogenesis. Expression of IL-19, a Th2 interleukin, can be induced in cultured EC and in vivo by local inflammation. Treatment of cultured human EC with IL-19 results in activation of STAT3, p44/42 MAPK, and Rac1. IL-19 treatment of EC results in increased cell spreading and enhanced migration. IL-19 is mitogenic for EC, and enhances cord-like structure formation and microvessel sprouting from aortic rings.

IL-35, a novel anti-inflammatory interleukin, is a dimeric protein with two subunits, IL-12A and Epstein-Barr virus induced 3 (EBI3). Anti-inflammatory cytokines IL-35 and IL-10 had very low expressions in non-stimulated tissues, whereas TGF-βs had high expression levels, suggesting that the latter cytokines, but not the former ones, are required for anti-inflammatory functions under non-stimulated "house-keeping" conditions.

References

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3. Yilma, A. N., Singh, S. R., Fairley, S. J., Taha, M. A., & Dennis, V. A. (2012). The anti-inflammatory cytokine, interleukin-10, inhibits inflammatory mediators in human epithelial cells and mouse macrophages exposed to live and UV-inactivated Chlamydia trachomatis. Mediators of inflammation, 2012.
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5. Li, X., Mai, J., Virtue, A., Yin, Y., Gong, R., Sha, X., ... & Wang, H. (2012). IL-35 is a novel responsive anti-inflammatory cytokine—a new system of categorizing anti-inflammatory cytokines. PloS one, 7(3), e33628.