IL22 Pathway
Interleukin-22 (IL-22) is a member of the IL-10 related cytokine family which includes IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26. It is generally secreted by Th17 and Th22 cells. Other immune cells like mast cells, NKT cells, natural killer22 (NK22) cells, lymphoid tissue inducer (LTi) and LTi-like cells also produce IL22. It exerts its effect on non-hematopoietic stromal cells including epithelial cells, keratinocytes, and hepatocytes.IL-22 is important for the host defense against extracellular pathogens, at mucosal surfaces as well as in tissue repair and wound healing (Ref. 1 and 2).
IL 22 signals through a type 2 cytokine receptor that comprised of a heterodimeric complex of IL22RA1 and IL-10R2 (IL-10Rb). A soluble IL-22R called IL-22-binding protein (IL-22BP) acts as a natural, soluble antagonist of IL-22. The complex of IL-22 and IL-22R induces a cascade of downstream signaling pathways. Major pathway activated by IL22 includes activation of Janus kinase 1 (JAK1) and non-receptor protein tyrosine kinase 2 (TYK2), which causes phosphorylation of STAT1, STAT3, and STAT5. Other pathways activated by IL22 include MAPK pathways (ERKs, JNKs and p38/SAPKs) and PI3K/AKT pathway. Upon activation of these signaling pathways, IL-22 enhances epithelial cell survival and regeneration and protects barrier integrity and microbial protection (Ref. 3 and 4).
TGFB can act as an inhibitor of IL-22 production. IRF4 also inhibits the production of IL-22 possibly through direct binding of the IL-22 promoter. In addition to TGFB, IL-27 and ICOS have both also been identified as inhibitors of IL-22 production. Transcription factor c-Maf also appears to be critical for the inhibition of IL-22 production (Ref.5). IL-22 plays an important role in inflammation, including chronic inflammatory diseases and infectious diseases. Recent studies have shown a possible role of Il22 in autoimmune diseases like Multiple Sclerosis, and in several cancers. Extensive research on cellular source of IL-22 and/or its signaling pathways may be important for development of IL-22 as a potential drug target (Ref.6). IL-22 has been proposed as a therapeutical target for several pathologies. IL-22 neutralizing antibodies as well as recombinant IL-22 are currently being tested in phase I and II clinical studies (Ref. 7).
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