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J. Biol. Chem., Vol. 279, Issue 40, 42192-42201, October 1, 2004

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Reverse Signaling through Membrane-bound Interleukin-15^*

Vadim Budagian¶, Elena Bulanova¶||**, Zane Orinska, Thomas Pohl, Ernest C. Borden, Robert Silverman||, and Silvia Bulfone-Paus

From the Department of Immunology and Cell Biology, Research Center Borstel, D-23845 Borstel, Germany, the Center for Cancer Drug Discovery and Development, Taussig Cancer Center, and the ^||Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, and WITA GmbH, Teltov D-14513, Germany

The results from this study implicate membrane-anchored interleukin (IL)-15 constitutively expressed on the cell surface of PC-3 human prostate carcinoma cells and interferon--activated human monocytes in reverse signaling upon stimulation with soluble IL-15 receptor- or anti-IL-15 antibodies, mediating the outside-to-inside signal transduction that involves the activation of members of the MAPK family (ERK and p38) and focal adhesion kinase. The presence of membrane-bound IL-15 was not dependent on the expression of the trimeric IL-15 receptor complex by these cells and resisted treatment with acidic buffer or trypsin. Reverse signaling through membrane-bound IL-15 considerably increased the production of several pro-inflammatory cytokines by monocytes, such as IL-6, IL-8, and tumor necrosis factor-, thereby indicating the relevance of this process to the complex immunomodulatory function of these cells. Furthermore, stimulation of transmembrane IL-15 also enhanced the transcription of IL-6 and IL-8 in the PC-3 cell line and promoted migration of PC-3 cells as well as LNCaP human prostate carcinoma cells stably expressing IL-15 on the cell surface. Thus, IL-15 can exist as a biologically active transmembrane molecule that possesses dual ligand-receptor qualities with a potential to induce bidirectional signaling. This fact highlights a new level of complexity in the biology of IL-15 and offers novel important insights into our understanding of the cellular responses modulated by this pleiotropic cytokine.

Received for publication, March 22, 2004 , and in revised form, July 9, 2004.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SFB415-A10 (to S. B.-P). 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.

^¶ Both authors contributed equally to this work.

^** To whom correspondence should be addressed: Dept. of Immunology and Cell Biology, Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany. Tel.: 49-4537-188-564; Fax: 49-4537-188-403; E-mail: ebulanova{at}fz-borstel.de.

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