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J. Biol. Chem., Vol. 282, Issue 5, 3014-3026, February 2, 2007

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Interleukin-31 and Oncostatin-M Mediate Distinct Signaling Reactions and Response Patterns in Lung Epithelial Cells^*

Souvik Chattopadhyay¹, Erin Tracy¹, Ping Liang, Olivier Robledo², Stefan Rose-John^¶, and Heinz Baumann³

From the Departments of Molecular and Cellular Biology and Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263 and the ^¶Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, D-24098 Kiel, Germany

Lung epithelial cells are primary targets of oncostatin M (OSM) and, to a lower degree, of interleukin (IL)-6 and IL-31, all members of the IL-6 cytokine family. The OSM receptor (OSMR) signals through activation of STAT and mitogen-activated protein kinase pathways to induce genes encoding differentiated cell functions, reduce cell-cell interaction, and suppress cell proliferation. IL-31 functions through the heteromeric IL-31 receptor, which shares with OSMR the OSMR subunit, but does not engage gp130, the common subunit of all other IL-6 cytokine receptors. Because the response of epithelial cells to IL-31 is unknown, the action of IL-31 was characterized in the human alveolar epithelial cell line A549 in which the expression of the ligand-binding IL-31R subunit was increased. IL-31 initiated signaling that differed from other IL-6 cytokines by the particularly strong recruitment of the STAT3, ERK, JNK, and Akt pathways. IL-31 was highly effective in suppressing proliferation by altering expression of cell cycle proteins, including up-regulation of p27^Kip1 and down-regulation of cyclin B1, CDC2, CDK6, MCM4, and retinoblastoma. A single STAT3 recruitment site (Tyr-721) in the cytoplasmic domain of IL-31R exerts a dominant function in the entire receptor complex and is critical for gene induction, morphological changes, and growth inhibition. The data suggest that inflammatory and immune reactions involving activated T-cells regulate functions of epithelial cells by IL-6 cytokines through receptor-defined signaling reactions.

Received for publication, October 13, 2006 , and in revised form, November 16, 2006.

^* This work was supported by NCI Grant CA085580 from the National Institutes of Health (to H. B.), Roswell Park Center Support Grant CA16056, and a Roswell Park Alliance grant (to H. B.). 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 Both authors contributed equally to this work.

² Present address: Centre Hospitalier de l'Université de Montréal Research Centre, Notre Dame Hospital, 1560 Sherbrooke East, Montreal, Quebec H2L 4M1, Canada.

³ To whom correspondence should be addressed: Dept. of Molecular and Cellular Biology, Elm and Carlton St., Buffalo, NY 14263. Tel.: 716-845-4587; Fax: 716-845-5908; E-mail: heinz.baumann{at}roswellpark.org.

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