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J. Biol. Chem., Vol. 278, Issue 40, 38829-38839, October 3, 2003

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Cellular Cholesterol Depletion Triggers Shedding of the Human Interleukin-6 Receptor by ADAM10 and ADAM17 (TACE)^*,

Vance Matthews, Björn Schuster, Stefan Schütze , Ingo Bussmeyer, Andreas Ludwig, Christian Hundhausen, Thorsten Sadowski, Paul Saftig, Dieter Hartmann , Karl-Josef Kallen ¶ and Stefan Rose-John ¶ ||

From the Biochemisches Institut, Christian Albrechts Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Institut für Immunologie, Christian Albrechts Universität zu Kiel, Michealisstrasse 5, D-24105 Kiel, Germany, and Center for Human Genetics, Leuven and Flanders Interuniversity, B-3000 Leuven, Belgium

Interleukin-6 (IL-6) activates cells by binding to the membrane-bound IL-6 receptor (IL-6R) and subsequent formation of a glycoprotein 130 homodimer. Cells that express glycoprotein 130, but not the IL-6R, can be activated by IL-6 and the soluble IL-6R which is generated by shedding from the cell surface or by alternative splicing. Here we show that cholesterol depletion of cells with methyl--cyclodextrin increases IL-6R shedding independent of protein kinase C activation and thus differs from phorbol ester-induced shedding. Contrary to cholesterol depletion, cholesterol enrichment did not increase IL-6R shedding. Shedding of the IL-6R because of cholesterol depletion is highly dependent on the metalloproteinase ADAM17 (tumor necrosis factor--converting enzyme), and the related ADAM10, which is identified here for the first time as an enzyme involved in constitutive and induced shedding of the human IL-6R. When combined with protein kinase C inhibition by staurosporine or rottlerin, breakdown of plasma membrane sphingomyelin or enrichment of the plasma membrane with ceramide also increased IL-6R shedding. The effect of cholesterol depletion was confirmed in human THP-1 and Hep3B cells and in primary human peripheral blood monocytes, which naturally express the IL-6R. For decades, high cholesterol levels have been considered harmful. This study indicates that low cholesterol levels may play a role in shedding of the membrane-bound IL-6R and thereby in the immunopathogenesis of human diseases.

Received for publication, October 16, 2002 , and in revised form, June 11, 2003.

^* This work was supported by Grants SFB415, Project B5, and KA1550/1-1 from the Deutsche Forschungsgemeinschaft (to S. R.-J. and K.-J. K.). 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.

The on-line version of this article (available at http://www.jbc.org) contains Figs. S1 and S2.

^¶ Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Biochemisches Institut, Christian Albrechts Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany. Tel.: 49-431-880-3336; Fax: 49-431-880-5007; E-mail: rosejohn{at}biochem.uni-kiel.de.

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