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J. Biol. Chem., Vol. 279, Issue 11, 10304-10315, March 12, 2004

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Functional Expression of the Interleukin-11 Receptor -Chain and Evidence of Antiapoptotic Effects in Human Colonic Epithelial Cells^*

Stephan Kiessling, Gerhard Muller-Newen, Sandra N. Leeb, Martin Hausmann, Heiko C. Rath, Jorn Strater¶, Tanja Spottl, Klaus Schlottmann, Johannes Grossmann, F. A. Montero-Julian||, Jurgen Scholmerich, Tilo Andus, Armin Buschauer**, Peter C. Heinrich, and Gerhard Rogler

From the Department of Internal Medicine I, University of Regensburg, 93042 Regensburg, Germany and ^**Institute of Pharmaceutical Chemistry, University of Regensburg, 93040 Regensburg, Germany, Institute of Biochemistry, RWTH 52074 Aachen, Pauwelsstrasse 30, Germany, ^||Imunotech: A Beckman-Coulter Company, 130 av. de Lattre de Tassigny, 13276 Marseille, Cedex 9, France, and ^¶Institute of Pathology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany

A tissue-protective effect of interleukin-11 (IL-11) for the intestinal mucosa has been postulated from animal models of inflammatory bowel disease (IBD). Despite the fact that the clinical usefulness of the anti-inflammatory effects of this cytokine is presently investigated in patients with IBD, there are no data available regarding the target cells of IL-11 action and the mechanisms of tissue protection within the human colonic mucosa. IL-11 responsiveness is restricted to cells that express the interleukin-11 receptor -chain (IL-11R) and an additional signal-transducing subunit (gp130). In this study, we identified the target cells for IL-11 within the human colon with a new IL-11R monoclonal antibody and investigated the functional expression of the receptor and downstream effects of IL-11-induced signaling. Immunohistochemistry revealed expression of the IL-11R selectively on colonic epithelial cells. HT-29 and colonic epithelial cells (CEC) constitutively expressed IL-11R mRNA and protein. Co-expression of the signal-transducing subunit gp130 was also demonstrated. IL-11 induced signaling through triggering activation of the Jak-STAT pathway without inducing anti-inflammatory or proliferative effects in colonic epithelial cells. However, IL-11 stimulation resulted in a dose-dependent tyrosine phosphorylation of Akt, a decreased activation of caspase-9, and a reduced induction of apoptosis in cultured CEC. In HLA-B27 transgenic rats treated with IL-11, a reduction of apoptotic cell numbers was found. This study demonstrates functional expression of the IL-11R restricted on CEC within the human colonic mucosa. IL-11 induced signaling through triggering activation of the Jak-STAT pathway, without inducing anti-inflammatory or proliferative effects. The beneficial effects of IL-11 therapy are likely to be mediated by CEC via activation of the Akt-survival pathway, mediating antiapoptotic effects to support mucosal integrity.

Received for publication, November 21, 2003

^* This work was supported by the Deutsche Forschungsgemeinschaft Grants AN168/3-2, SFB542, and the BMBF Kompetenznetzwerk: Chronisch-entzündliche Darmerkrankungen. 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.

To whom correspondence should be addressed: Dept. of Internal Medicine I, University of Regensburg, 93042 Regensburg, Germany. Tel.: 49-941-944-7180; Fax: 49-941-944-7179; E-mail: gerhard.rogler{at}klinik.uni-regensburg.de.

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