Interleukin-8 secretion by fibroblasts induced by low density lipoproteins is p38 MAPK-dependent and leads to cell spreading and wound closure.
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.
Dobreva
Iveta
I
Department of Cellular Biology and Morphology, Faculty of Biology and Medicine, Lausanne University, 1005 Lausanne, Switzerland.
Waeber
Gérard
G
James
Richard W
RW
Widmann
Christian
C
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*
D016209:Interleukin-8; D008077:Lipoproteins, LDL; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D048051:p38 Mitogen-Activated Protein Kinases