Immune response IL-22 signaling pathway
IL-22 signaling pathway
Interleukin-22 ( IL-22 ) is a member of the IL-10 family of cytokines. Themajor sources of IL-22 are activated T cells, especially upon type 1 polarization,and natural killer (NK) cells [1], [2].
IL-22 acts via a heterodimeric receptor complex ( IL-22 receptor )consisting of Interleukin 22 receptor, alpha 1 subunit ( IL22RA1 ) and Interleukin10 receptor, beta subunit ( IL10RB ). Neither resting, nor activated immune cellsexpress IL22RA1, or respond to IL-22. In contrast, tissue cells at outerbody barriers, i.e., of the skin, kidney, and the digestive and respiratory systems aretargets of this cytokine. IL-22 produced by immune cells regulates tissueprotection and homeostasis by promoting the anti-microbial defense, protecting againstdamage, and reorganizing non-immune tissues [3], [4].
In addition to the cell surface associated IL-22 receptor complex, there is asecreted ('soluble'), single-chain Interleukin 22 receptor, alpha 2 ( IL-22RA2 ).IL-22RA2 prevents binding of IL-22 to the functional cell surface IL-22receptor and neutralizes IL-22 activity. IL-22RA2 also blocks inductionof the Suppressor of cytokine signaling-3 ( SOCS3 ) gene expression byIL-22 [4].
IL-22 is expressed in T cells activated by either T cell receptor ( TCRalpha/beta ) stimulation in response to antigen presentation by Majorhistocompatibility complex, class II ( MHC class II ), or stimulation with othercytokines, e.g., Interleukin-9 (IL-9) [5], [2], [4]. IL-22 expression is markedly enhanced in Th1 polarized populations of Tcells rather than Th2 CD4 cells [2]. IL-22 is also expressed by Th17cells, a distinct lineage of effector CD4+ T cells characterized by their production ofInterleukin-17 (IL-17). IL-22 synergizes with IL-17 to regulate genes associatedwith skin innate immunity [6].
Interleukin-2 ( IL-2 ) and Interleukin-12 ( IL-12 ) secreted by CD4+ Tcells and antigen-presenting cells, respectively, act on NK cells that can produceIL-22 in response to IL-2 and IL-12 [1]. IL-2signaling pathway includes IL-2 receptor/ Janus kinases 1 and 3 ( JAK1 andJAK3 )/ 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 transducerand activator of transcription 4 ( STAT4 ) [7], [8],[4].
Although activated CD4+ T cells and NK cells secrete IL-22, this cytokine actsexclusively on certain tissue cells. If the production occurs in the lymph nodes, thecytokine binds to IL-22RA2 constitutively expressed by the lymph nodes andprobably acts as a carrier for IL-22 to transport this cytokine to its targetcells [4].
The IL-22 that is produced in infected tissues mostly acts directly on theadjacent tissue cells. IL-22 binding to IL-22 receptor complex leads to theactivation of the receptor-associated Janus kinases JAK1 and Tyk2,followed by activation of transcription factors STAT3, and often STAT1and/or STAT5. These molecules are then phosphorylated by JAK1 andTyk2 to form homodimers that immigrate into the nucleus to induce the expressionof specific genes and therefore modulate the cell activities [2], [3], [4].
STAT3 induces expression of SOCS3, which can negatively regulateJAK1/ STAT3 signaling [9]. STAT3 also up-regulatesexpression 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 )) andmitogenic (e.g., v-Myc myelocytomatosis viral oncogene homolog ( c-Myc )) proteins[10].
In addition to JAK/STAT signaling, activation of the three major MAP kinase pathways(Mitogen-activated protein kinases 8-10 ( JNK(MAPK8-10) ), Mitogen-activatedprotein kinases 11-14 ( p38 MAPK ) and Mitogen-activated protein kinases 3 and 1 (ERK1/2 )) is also required for maximum IL-22-induced transactivation ofSTAT3 by yet unknown mechanism, and is possibly required for activation ofActivating protein 1 ( c-Jun/c-Fos ), heterodimeric transcription factorconsisting of Jun oncogene ( c-Jun ) and v-Fos FBJ murine osteosarcoma viraloncogene homolog ( c-Fos ), to elicit expression of proinflammatory cytokines[11], [12], [4].
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