IL-10 and IL-10 receptor defects in humans

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IL-10 and IL-10 receptor defects in humans (1)

Interleukin (IL)-10 may be considered the most important anti-inflammatory cytokine in humans. Secreted by a variety of cells including monocytes, macrophages, dendritic cells, T cells, B cells, granulocytes, epithelial cells, keratinocytes, and mast cells. Since IL-10 is a critical player in maintaining immune system balance, mutations in IL-10 or components of its signaling pathway that reduce or abolish their anti-inflammatory properties were thought to be involved in the pathogenesis of hyperinflammatory disorders such as rheumatoid arthritis or inflammatory bowel disease (IBD). Certain variants of IBD or IL-10 and IL-10 receptor (IL-10R)-deficiency are monogenic autosomal recessive diseases. Loss-of-function mutations in either the IL-10 or IL-10R gene cause severe early-onset IBD in humans demonstrates the importance of IL-10 and shows that loss of IL-10 signaling significantly impairs life.

IL-10 dimerizes and binds to a cell-bound cytokine receptor made up of two molecules of the IL-10R -chain (IL-10R1) and two molecules of the accessory IL-10R -chain (IL-10R2). IL-10R2 is shared by several other cytokines, including IL-22, IL-26, and the -interferons IL-28A/B and IL-29.

In view of the life-threatening clinical course of the IL-10R mutations, allogeneic hematopoietic stem cell transplantation (HSCT) was proposed. Mutations in IL-10R2 result in more severe phenotypes than mutations in either IL-10R1 or IL-10. In particular, lack of IL-22 signaling may be additive to the phenotype of IL-10R2 deficiency because IL-22 protects against colitis and significantly improved colitis in a murine model of UC. IL-22 upregulates expression of the antimicrobial proteins RegIII-beta and RegIII-gamma and enhances mucus production in murine colonic epithelial cells, which thereby maintains the epithelial barrier and prevents infection by intestinal bacterial pathogens. IL-22 induces production of IL-10; a similar activity was also found for IL-26.

Defects in the IL-10R may be easily tested by functional assays. PBMCs from healthy individuals show strong phosphorylation of STAT3 upon stimulation with IL-10, whereas PBMCs from IL-10R–deficient patients do not. In contrast to patients with IL-10R mutations, where administration of exogenous IL-10 has no effect at all, stimulation by IL-10 completely abrogates LPS-mediated TNF-alpha release in PBMCs from healthy controls.

1. E.-O. Glocker, D. Kotlarz, C. Klein, N. Shah, B. Grimbacher, IL-10 and IL-10 receptor defects in humans. Ann. N. Y. Acad. Sci. 1246, 102–107 (2011).

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