The Interleukin-22/STAT3 Pathway Potentiates Expression of Inducible Nitric-oxide Synthase in Human Colon Carcinoma Cells

Abstract

Interleukin (IL)2 -22 is a newly described member of the IL-10 family of cytokines that is produced by T and NK cells under conditions of immunoactivation. Initiation of the Jak1/Tyk2/ signal transducer and activator of transcription (STAT) 3 pathway appears to be the major mode of IL-22 signal transduction (1-4), although activation of STAT1 (5, 6), mitogen-activated protein kinases (5-7), nuclear factor B (NF-B) (8), activator protein-1 (8), and protein kinase B (6) has been related to this cytokine under specific conditions. IL-22 signaling is established by binding of the cytokine to its heterodimeric receptor complex consisting of IL-22R1 and IL-10R2 (2, 3). Because IL-10R2 is a ubiquitous protein, cellular IL-22 responsiveness is mainly determined by expression of the IL-22R1 receptor chain. Interestingly, IL-22R1 expression is restricted to nonleukocytic cells (9 -11). Therefore, IL-22 appears to be unique among a vast array of cytokines in that this protein is incapable of mediating autocrine or paracrine functions between leukocytes but is rather specialized to transmit information between leukocytes and the nonleukocytic cell compartment. This distinctive biological characteristic essentially discriminates IL-22 from another major activator of the STAT3 signaling system, namely IL-6 (12). Cell types identified to be responsive to IL-22 include synoviocytes (7), pancreatic acinar cells (11), hepatocytes (5, 13, 14), colonic epithelial myofibroblasts (8), and in particular cells of epithelial origin such as keratinocytes (10,15), lung carcinoma cells (16), and colon carcinoma cells (6,17). Proteins that have been reported to be inducible by IL-22 include pro-inflammatory and pro-angiogenic mediators such as IL-8 and enzymes that are involved in cell migration and tissue remodeling such as matrix metalloprotease-1 and -3 (6, 8), effector molecules of innate immunity such as ␤-defensins (10), and immunosuppressive modulators such as IL-10 (17) and SOCS proteins (17, 18). IL-22-induced STAT3 has been associated with induction of the acute phase response (13), with proliferation, and with protection from cell death (6, 14). Interestingly, constitutive activation of the STAT3 pathway is characteristic for numerous human malignancies. Based on the capabilities of this transcription factor to inhibit apoptosis and to promote cell proliferation, STAT3 is actually considered an oncogenic protein (12,19,20).Inducible nitric-oxide synthase (iNOS) and its volatile enzymatic product nitric oxide (NO) have been identified as potential promoters of tumor growth in a variety of human neoplasia, among other colorectal cancers (20 -24). The ability of iNOS to * This work was supported by Deutsche Forschungsgemeinschaft Grants GK1172 Biologicals and SFB 553. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.

Co‐operative action of interleukin‐10 and interferon‐γ to regulate dendritic cell functions

“…37 Interleukin-22 induced marked phosphorylation of STAT3 in these cells and short interfering RNA technology identified that STAT3 was crucial for the synergy in iNOS expression by DLD-1 cells. In the present study, IL-10 induced marked phosphorylation of STAT3 and synergistically enhanced IFNc-induced iNOS expression in DCs.…”

Involvement of the IL-22/REG Iα axis in ulcerative colitis

“…29,30 Interestingly, IL-22 is thought to be produced by immune cells such as Th17, NK, 31,32 anti-bacterial peptides (b-defensin, calgranulins), 33,34 and mucin (MUC1, -3, -10, and -13). 35,36 In this study, we examined whether IL-22 stimulation is responsible for REG Ia overexpression in the colonic epithelium in UC mucosa, because in several gene tip analyses REG Ia has been proven to be a distinctly upregulated gene in the colonic epithelium of patients with UC.…”

Simian immunodeficiency virus–induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut

“…1c and data not shown). IL-22 and IFN-γ synergize to induce inducible nitric oxide synthase (iNOS) expression 13 , whose mRNA levels were markedly increased after S. typhimurium infection (Fig. 1c).…”