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J. Biol. Chem., Vol. 282, Issue 22, 16006-16015, June 1, 2007

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

Elisabeth Ziesché, Malte Bachmann, Hartmut Kleinert, Josef Pfeilschifter, and Heiko Mühl¹

From the Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt am Main, 60590 Frankfurt am Main and the Department of Pharmacology, Johannes Gutenberg Universität, 55101 Mainz, Germany

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)- 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 IFN, STAT1 phosphorylation by IL-22 was insufficient. IL-22 did not stabilize IL-1/tumor necrosis factor-/IFN-induced iNOS mRNA. IL-22 also failed to amplify expression of the prototypic IFN-inducible parameters IL-18-binding protein and CXCL-10, indicating that IL-22 is not a general amplifier of IFN 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-B. 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.

Received for publication, November 30, 2006 , and in revised form, April 2, 2007.

^* 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. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Tel.: 49 69 6301 6955; Fax: 49 69 6301 7942; E-mail: H.Muehl{at}em.uni-frankfurt.de.

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