Immune response - IL-22 signaling pathway

IL-22 signaling pathway

Interleukin-22 (IL-22) is a member of the IL-10 family of cytokines. The major 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 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 [3], [4].

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 [4].

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) [2], [4], [5]. IL-22 expression is markedly enhanced in Th1 polarized populations of T cells rather than Th2 CD4 cells [2]. 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 [6].

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 [1]. 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) [4], [7], [8].

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 [4].

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 [2], [3], [4].

STAT3 induces expression of SOCS3, which can negatively regulate JAK1/ STAT3 signaling [9]. 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 [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-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 [4], [11], [12].

References:

1. Wolk K, Kunz S, Asadullah K, Sabat R
   Cutting edge: immune cells as sources and targets of the IL-10 family members? Journal of immunology (Baltimore, Md. : 1950) 2002 Jun 1;168(11):5397-402
2. Gurney AL
   IL-22, a Th1 cytokine that targets the pancreas and select other peripheral tissues. International immunopharmacology 2004 May;4(5):669-77
3. Nagem RA, Ferreira Junior JR, Dumoutier L, Renauld JC, Polikarpov I
   Interleukin-22 and its crystal structure. Vitamins and hormones 2006;74:77-103
4. Wolk K, Sabat R
   Interleukin-22: a novel T- and NK-cell derived cytokine that regulates the biology of tissue cells. Cytokine & growth factor reviews 2006 Oct;17(5):367-80
5. Dumoutier L, Louahed J, Renauld JC
   Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. Journal of immunology (Baltimore, Md. : 1950) 2000 Feb 15;164(4):1814-9
6. Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, Fouser LA
   Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. The Journal of experimental medicine 2006 Oct 2;203(10):2271-9
7. Yu CR, Young HA, Ortaldo JR
   Characterization of cytokine differential induction of STAT complexes in primary human T and NK cells. Journal of leukocyte biology 1998 Aug;64(2):245-58
8. Sudarshan C, Galon J, Zhou Y, O'Shea JJ
   TGF-beta does not inhibit IL-12- and IL-2-induced activation of Janus kinases and STATs. Journal of immunology (Baltimore, Md. : 1950) 1999 Mar 1;162(5):2974-81
9. Nagalakshmi ML, Rascle A, Zurawski S, Menon S, de Waal Malefyt R
   Interleukin-22 activates STAT3 and induces IL-10 by colon epithelial cells. International immunopharmacology 2004 May;4(5):679-91
10. Radaeva S, Sun R, Pan HN, Hong F, Gao B
    Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology (Baltimore, Md.) 2004 May;39(5):1332-42
11. Lejeune D, Dumoutier L, Constantinescu S, Kruijer W, Schuringa JJ, Renauld JC
    Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10. The Journal of biological chemistry 2002 Sep 13;277(37):33676-82
12. Andoh A, Zhang Z, Inatomi O, Fujino S, Deguchi Y, Araki Y, Tsujikawa T, Kitoh K, Kim-Mitsuyama S, Takayanagi A, Shimizu N, Fujiyama Y
    Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology 2005 Sep;129(3):969-84