IL-2, IL10RB, IL-12 receptor, c-Myc, STAT5, STAT4, JAK3, JAK1, ERK1/2, CD4, STAT1, c-Fos, CD86, STAT3, c-Jun/c-Fos, JNK(MAPK8-10), c-Jun, CD28, MHC class II, p38 MAPK, IL-22RA2, IL-22, IL-2 receptor, IL-22 receptor, TCR alpha/beta, Bcl-2, JAK2, STAT5, SOCS3, Tyk2, IL22RA1, Bcl-XL, Tyk2, IL-12, Mcl-1, JAK1
IL-22 signaling pathway
IL-22 acts via a heterodimeric receptor complex ( IL-22 receptor ) consisting of Interleukin 22 receptor, alpha 1 subunit ( IL22RA1 ) and Interleukin 10 receptor, beta subunit ( IL10RB ). Neither resting, nor activated immune cells express IL22RA1, or respond to IL-22. In contrast, tissue cells at outer body barriers, i.e., of the skin, kidney, and the digestive and respiratory systems are targets of this cytokine. IL-22 produced by immune cells regulates tissue protection and homeostasis by promoting the anti-microbial defense, protecting against damage, and reorganizing non-immune tissues , .
In addition to the cell surface associated IL-22 receptor complex, there is a secreted ('soluble'), single-chain Interleukin 22 receptor, alpha 2 ( IL-22RA2 ). IL-22RA2 prevents binding of IL-22 to the functional cell surface IL-22 receptor and neutralizes IL-22 activity. IL-22RA2 also blocks induction of the Suppressor of cytokine signaling-3 ( SOCS3 ) gene expression by IL-22 .
IL-22 is expressed in T cells activated by either T cell receptor ( TCR alpha/beta ) stimulation in response to antigen presentation by Major histocompatibility complex, class II ( MHC class II ), or stimulation with other cytokines, e.g., Interleukin-9 (IL-9) , , . IL-22 expression is markedly enhanced in Th1 polarized populations of T cells rather than Th2 CD4 cells . IL-22 is also expressed by Th17 cells, a distinct lineage of effector CD4+ T cells characterized by their production of Interleukin-17 (IL-17). IL-22 synergizes with IL-17 to regulate genes associated with skin innate immunity .
Interleukin-2 ( IL-2 ) and Interleukin-12 ( IL-12 ) secreted by CD4+ T cells and antigen-presenting cells, respectively, act on NK cells that can produce IL-22 in response to IL-2 and IL-12 . IL-2 signaling pathway includes IL-2 receptor/ Janus kinases 1 and 3 ( JAK1 and JAK3 )/ Signal transducers and activators of transcription 5 ( STAT5 ) activation. IL-12 signaling pathway involves activation of IL-12 receptor/ Janus kinase 2 and Tyrosine kinase 2 ( JAK2 and Tyk2 )/ Signal transducer and activator of transcription 4 ( STAT4 ) , , .
Although activated CD4+ T cells and NK cells secrete IL-22, this cytokine acts exclusively on certain tissue cells. If the production occurs in the lymph nodes, the cytokine binds to IL-22RA2 constitutively expressed by the lymph nodes and probably acts as a carrier for IL-22 to transport this cytokine to its target cells .
The IL-22 that is produced in infected tissues mostly acts directly on the adjacent tissue cells. IL-22 binding to IL-22 receptor complex leads to the activation of the receptor-associated Janus kinases JAK1 and Tyk2, followed by activation of transcription factors 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 , , .
STAT3 induces expression of SOCS3, which can negatively regulate JAK1/ STAT3 signaling . STAT3 also up-regulates expression of a variety of anti-apoptotic (e.g., B-cell CLL/lymphoma 2 ( Bcl-2 ), BCL2-like 1 ( Bcl-XL ), Myeloid cell leukemia sequence 1 ( Mcl-1 )) and mitogenic (e.g., v-Myc myelocytomatosis viral oncogene homolog ( c-Myc )) proteins .
In addition to JAK/STAT signaling, activation of the three major MAP kinase pathways (Mitogen-activated protein kinases 8-10 ( JNK(MAPK8-10) ), Mitogen-activated protein kinases 11-14 ( p38 MAPK ) and Mitogen-activated protein kinases 3 and 1 ( ERK1/2 )) is also required for maximum IL-22-induced transactivation of STAT3 by yet unknown mechanism, and is possibly required for activation of Activating protein 1 ( c-Jun/c-Fos ), heterodimeric transcription factor consisting of Jun oncogene ( c-Jun ) and v-Fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ), to elicit expression of proinflammatory cytokines , , .