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J. Biol. Chem., Vol. 279, Issue 39, 40368-40375, September 24, 2004

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Natural Soluble Interleukin-15R Is Generated by Cleavage That Involves the Tumor Necrosis Factor--converting Enzyme (TACE/ADAM17)^*

Vadim Budagian¶, Elena Bulanova¶||, Zane Orinska, Andreas Ludwig**, Stefan Rose-John**, Paul Saftig**, Ernest C. Borden, and Silvia Bulfone-Paus

From the Center for Cancer Drug Discovery and Development, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio 44195, the Department of Immunology and Cell Biology, Research Center Borstel, D-23845 Borstel, Germany, and the ^**Institute of Biochemistry, Christian-Albrechts-University, D-24118 Kiel, Germany

This study shows that the high affinity -chain of the interleukin (IL)-15 receptor exists not only in membrane-anchored but also in soluble form. Soluble IL-15R (sIL-15R) can be detected in mouse sera and cell-conditioned media by enzyme-linked immunosorbent assay and by immunoprecipitation and Western blotting. This protein has a molecular mass of about 30 kDa because of the presence of a single N-glycosylation site, which is reduced to 26 kDa after N-glycosidase treatment. Transmembrane IL-15R is constitutively converted into its soluble form by proteolytic cleavage that involves tumor necrosis factor--converting enzyme (TACE), and this process is further enhanced by phorbol 12-myristate 13-acetate (PMA) stimulation. The hydroxamate GW280264X, which is capable of blocking TACE and the closely related disintegrin-like metalloproteinase 10 (ADAM10), effectively inhibited both spontaneous and PMA-inducible cleavage of IL-15R, whereas GI254023X, which preferentially blocks ADAM10, was ineffective. Overexpression of TACE but not ADAM10 in COS-7 cells enhanced the constitutive and PMA-inducible cleavage of IL-15R. Moreover, murine fibroblasts deficient in TACE but not ADAM10 expression exhibited a significant reduction in the spontaneous and inducible IL-15R shedding, whereas a reconstitution of TACE in these cells restored the release of sIL-15R, thereby suggesting that TACE-mediated proteolysis may represent a major mechanism for sIL-15R generation in mice. The existence of natural sIL-15R offers novel insights into the complex biology of IL-15 and envisages a new level for therapeutic intervention.

Received for publication, April 14, 2004 , and in revised form, June 21, 2004.

^* This work was supported in part by Sonderforschungsbereich 415 project 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: Department of Immunology and Cell Biology, Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany. Tel.: 49-4537-188564; Fax: 49-4537-188403; Email: ebulanova{at}fz-borstel.de.

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