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J. Biol. Chem., Vol. 281, Issue 1, 199-205, January 6, 2006

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Interleukin-8 Secretion by Fibroblasts Induced by Low Density Lipoproteins Is p38 MAPK-dependent and Leads to Cell Spreading and Wound Closure^*

Iveta Dobreva, Gérard Waeber, Richard W. James¶, and Christian Widmann1

From the Department of Cellular Biology and Morphology, Faculty of Biology and Medicine, Lausanne University, 1005 Lausanne, Switzerland, the Department of Internal Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland, and the ^¶Lipid Laboratory, Clinical Diabetes Unit, University Hospital, 1211 Geneva 14, Switzerland

We have previously reported (Dobreva, I., Waeber, G., Mooser, V., James, R. W., and Widmann, C. (2003) J. Lipid Res. 44, 2382–2390) that low density lipoproteins (LDLs) induce activation of the p38 MAPK pathway, resulting in fibroblast spreading and lamellipodia formation. Here, we show that LDL-stimulated fibroblast spreading and wound sealing are due to secretion of a soluble factor. Using an antibody-based human protein array, interleukin-8 (IL-8) was identified as the main cytokine whose concentration was increased in supernatants from LDL-stimulated cells. Incubation of supernatants from LDL-treated cells with an anti-IL-8 blocking antibody completely abolished their ability to induce cell spreading and mediate wound closure. In addition, fibroblasts treated with recombinant IL-8 spread to the same extent as cells incubated with LDL or supernatants from LDL-treated cells. The ability of LDL and IL-8 to induce fibroblast spreading was mediated by the IL-8 receptor type II (CXCR-2). Furthermore, LDL-induced IL-8 production and subsequent wound closure required the activation of the p38 MAPK pathway, because both processes were abrogated by a specific p38 inhibitor. Therefore, the capacity of LDLs to induce fibroblast spreading and accelerate wound closure relies on their ability to stimulate IL-8 secretion in a p38 MAPK-dependent manner. Regulation of fibroblast shape and migration by lipoproteins may be relevant to atherosclerosis that is characterized by increased LDL cholesterol levels, IL-8 production, and extensive remodeling of the vessel wall.

Received for publication, August 11, 2005 , and in revised form, October 17, 2005.

^* This work was supported by the Botnar Foundation (Lausanne, Switzerland), grants from the Leenaards Foundation (to C. W. and R. W. J), and by Swiss National Research Foundation Grant 310000-109281 (to G. W. and C. W.). 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 a supplemental movie showing the response of LDL-treated cells to wounding.

¹ To whom correspondence should be addressed: Dept. of Cellular Biology and Morphology, Biology and Medicine Faculty, University of Lausanne, Bugnon 9, 1005 Lausanne, Switzerland. Tel.: 41-21-692-5123; Fax: 41-21-692-5255; E-mail: Christian.Widmann{at}unil.ch.

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