IL-22 Signaling

Interleukin 22 (IL-22/IL-TIF) 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.In humans, IL-22 signals through a heteroduplex receptor consisting of IL-22R and IL-10R. 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 β is a typical short chain component, with only 76 amino acids in the cytoplasmic domain, whose main function seems to consist in recruiting TYK2. 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 β chain and mediates IL-22 signaling. IL-22 and its receptor induce activation of JAK1 and TYK2 but not JAK2. JAK1 further causes phosphorylation of STAT1, STAT3, and STAT5 on tyrosine residues, which then migrate to the nucleus, where they activate the transcription of a number of genes.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 and IL-22RA2, 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. Lipopolysaccharide (LPS) induces IL-22 expression, which indicates the role of IL-22 in inflammatory response. 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 Pancreatitis-Associated Protein-1 (PAP1), suggesting a link between IL-22 and pancreatic immune disease.