IL-22 Pathway
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IL-22 Pathway

IL-22/IL-TIF (Interleukin-22/IL-10-related T-Cell-derived Inducible Factor) is a novel cytokine belonging to the IL-10 family. IL-22 induces the production of acute-phase reactants in liver and pancreas, suggesting its involvement in the generation of inflammatory and allergic responses. Human IL-22 is a 179 aa polypeptide that contains a 33 aa ss and a 146 aa mature region. The mature molecule contains three potential N-linked glycosylation sites plus four cysteines, only two of which are conserved in IL-10 (Ref.1).

In humans, IL-22 signals through a heteroduplex receptor consisting of IL-22R (IL-22 Receptor/CRF2-9/zcytor11 and IL-TIF-R1 chain) and IL-10R (IL-10 Receptor/CRF2-4). Based on limited sequence identity in their extracellular ligand binding domains, both receptors are members of the class 2-cytokine receptor family. As implied by its name, IL-10R2 was first identified as an essential component of the IL-10R complex. IL-10R beta is a typical short chain component, with only 76 amino acids in the cytoplasmic domain, whose main function seems to consist in recruiting the TYK2 (non-receptor protein Tyrosine Kinase-2) (Ref.2). The IL-22R is a 574 aa type I transmembrane protein that contains a 574 aa extracellular region, a 23 aa transmembrane segment, and a 346 aa cytoplasmic domain. IL-22R forms a complex with IL-10R beta chain and mediates IL-22 signaling. IL-22 and its receptor induce activation of JAK1 (Janus Kinase-1) and TYK2 but not JAK2. JAK1 further causes phosphorylation of STAT1 (Signal Transducers and Activators of Transcription Factor-1), STAT3, and STAT5 on tyrosine residues, which then migrate to the nucleus, where they activate the transcription of a number of genes (Ref.3).

Other signaling pathways that are recruited by this receptor are MAPK (Mitogen Activated Protein Kinase), p90RSK and p38. A soluble form of IL-22R, also termed IL-22BP (IL-22 Binding Protein) and IL-22RA2 (IL-22 Receptor-Alpha2), was identified very recently. IL-22BP prevents binding of IL-22 to the functional cell surface IL-22R complex and neutralizes IL-22 activity. IL-22BP also blocked induction of the SOCS3 (Suppressors Of Cytokine Signaling-3) gene expression by IL-22. LPS (Lipopolysaccharide) induces IL-22 expression, which indicates the role of IL-22 in inflammatory response (Ref.4). Beside hepatocytes, other cell types such as intestinal and lung epithelial cells respond to IL-22, suggesting that IL-22 might have pleiotropic activities during inflammatory or immune responses. IL-22 also upregulates PAP1 (Pancreatitis-Associated Protein-1), suggesting a link between IL-22 and pancreatic immune disease (Ref.5).