title: Attenuation of the acute inflammatory response by dual specificity phosphatase 1 by inhibition of p38 MAP kinase.
abstract: Dual specificity phosphatase 1 (DUSP1) dephosphorylates and, hence, regulates the activity of MAP kinases. The present study investigated the effect of DUSP1 on inflammatory gene expression and on the development of carrageenan-induced inflammation. It was found that DUSP1 expression was increased by LPS, and the down-regulation of DUSP1 by siRNA enhanced the phosphorylation of p38 MAPK, while JNK phosphorylation was not affected in murine macrophages. LPS-induced interleukin (IL)-6, tumor-necrosis factor (TNF) and cyclooxygenase-2 (COX2) expression were enhanced in bone marrow-derived macrophages (BMMs) from DUSP1(-/-) mice as compared to those from wild-type mice. In addition, down-regulation of DUSP1 by siRNA enhanced IL-6, TNF and COX2 expression in J774 macrophages, while p38 MAPK inhibitors SB202190 and BIRB 796 inhibited the expression of those inflammatory factors. In vivo, the intensity of the carrageenan-induced paw edema reaction was increased in DUSP1(-/-) mice as compared to the wild-type animals. In conclusion, DUSP1 is an important negative regulator of the acute inflammatory response by limiting p38 MAPK, and compounds which enhance DUSP1 expression or activity may hold a promise as anti-inflammatory drugs.
authors.affiliation: The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland. riku.korhonen@uta.fi
authors.forename: Riku
authors.initials: R
authors.lastname: Korhonen
authors.forename: Tuija
authors.initials: T
authors.lastname: Turpeinen
authors.forename: Ville
authors.initials: V
authors.lastname: Taimi
authors.forename: Riina
authors.initials: R
authors.lastname: Nieminen
authors.forename: Antonis
authors.initials: A
authors.lastname: Goulas
authors.forename: Eeva
authors.initials: E
authors.lastname: Moilanen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002351:Carrageenan / Q000633:toxicity; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007509:Irritants / Q000633:toxicity; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D007509:Irritants; D034741:RNA, Small Interfering; D002351:Carrageenan; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse