title: Interleukin-8 secretion by fibroblasts induced by low density lipoproteins is p38 MAPK-dependent and leads to cell spreading and wound closure.
abstract: 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.
authors.affiliation: Department of Cellular Biology and Morphology, Faculty of Biology and Medicine, Lausanne University, 1005 Lausanne, Switzerland.
authors.forename: Iveta
authors.initials: I
authors.lastname: Dobreva
authors.forename: Gérard
authors.initials: G
authors.lastname: Waeber
authors.forename: Richard W
authors.initials: RW
authors.lastname: James
authors.forename: Christian
authors.initials: C
authors.lastname: Widmann
mesh_terms: D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism; D019898:Autocrine Communication / Q000187:drug effects / Q000276:immunology; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D012867:Skin / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D016209:Interleukin-8; D008077:Lipoproteins, LDL; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D048051:p38 Mitogen-Activated Protein Kinases