IL-22 Pathway

IL-22 triggers intracellular signals by binding to a heterodimeric receptor complex that is composed of IL-22RA1(IL-22 Receptor/CRF2-9/zcytor11 and IL-TIF-R1 chain) and IL-10R2 (IL-10Recepto/CRF2–4). Although IL-10R2 is ubiquitously expressed, IL-22RA1 is expressed in a relatively restricted pattern, being found at relatively high levels in the pancreas, small intestine, colon, kidney, and liver. Importantly, IL-22RA1 is not detectable in immune cells including monocytes, resting or activated B/T cells, natural killer cells, macrophages, and dendritic cells. IL-22 is known to activate a number of signaling pathways, including that of STAT3 and mitogen-activated protein kinase [29,38–41]. On the basis of the current understanding of the biology of IL-22, it is believed that IL-22 produced by T cells plays an important role in enhancing innate immunity and tissue repair [2].

IL-22 binding to the IL-22 receptor complex leads to the activation of the receptor-associated Janus kinases JAK1 and Tyk2, followed by activation of transcription factor STAT3, and often STAT1 and/or STAT5. These molecules are then phosphorylated by JAK1 and Tyk2 to form homodimers that immigrate into the nucleus to induce the expression of specific genes and therefore modulate the cell activities [3,4]. 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) or IL-22RA2 (IL-22 Receptor-Alpha2) 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 [5,6]. IL-22 also acts synergistically with tumor necrosis factor-alpha, IL-1beta, or IL-17. Importantly, IL-22 does not serve the communication between immune cells. It mainly acts on epithelial cells and hepatocytes, where it favors the antimicrobial defense, regeneration, and protection against damage and induces acute phase reactants and some chemokines [4].

IL-22 signaling leads to activation of proliferative and/or anti-apoptotic programs, allowing maintenance of epithelial barriers, such as those of the lungs or gastrointestinal tract during inflammation. IL-22 also induces tissue expression of acute inflammatory proteins, mucins, or antimicrobial peptides, which are important for tissues to maintain their integrity during inflammation, allowing for proper organ function and sequestration of potential pathogens [7].