The interleukin-22/STAT3 pathway potentiates expression of inducible nitric-oxide synthase in human colon carcinoma cells.
Inducible nitric-oxide synthase (iNOS) has been identified as a marker and mediator of disease in human colonic inflammation and carcinogenesis. Accordingly, identification of mediators that trigger iNOS in colon carcinoma/epithelial cells is an important topic of current research. Here we demonstrate that interleukin (IL)-22, a newly described member of the IL-10 cytokine family, potently synergizes with interferon (IFN)-gamma for iNOS expression in human DLD-1 colon carcinoma cells. Detection of both IL-22 receptor chains and STAT3 phosphorylation proved robust IL-22 responsiveness of these cells. Short interfering RNA technology identified STAT3 as being crucial for up-regulation of iNOS. Compared with IFNgamma, STAT1 phosphorylation by IL-22 was insufficient. IL-22 did not stabilize IL-1beta/tumor necrosis factor-alpha/IFNgamma-induced iNOS mRNA. IL-22 also failed to amplify expression of the prototypic IFNgamma-inducible parameters IL-18-binding protein and CXCL-10, indicating that IL-22 is not a general amplifier of IFNgamma functions. This assumption is furthermore supported by the observation that IL-22 was unable to enhance cellular activation of the pro-inflammatory transcription factor nuclear factor-kappaB. In contrast, IL-22 increased iNOS promoter activation as detected by using DLD-1 cells stably transfected with a corresponding 16-kb promoter construct (pNOS2(16)-Luc). IL-22 likewise enhanced iNOS in Caco-2 colon carcinoma cells. With IL-22 we introduce a novel potent determinant of iNOS expression in human colon carcinoma/epithelial cells. Considering the eminent functions of STAT3 and iNOS in inflammation and carcinogenesis, IL-22 may represent a novel target for immunotherapeutic intervention.
Ziesché
Elisabeth
E
Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt am Main, 60590 Frankfurt am Main, Germany.
Bachmann
Malte
M
Kleinert
Hartmut
H
Pfeilschifter
Josef
J
Mühl
Heiko
H
D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007167:Immunotherapy; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007378:Interleukins / Q000494:pharmacology* / Q000627:therapeutic use; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D018123:Receptors, Interleukin / Q000096:biosynthesis; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000097043:Interleukin-22
D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D007378:Interleukins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018123:Receptors, Interleukin; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C118370:interleukin-18 binding protein