Activation of p38 MAPK suppresses matrix metalloproteinase-1 gene expression induced by platelet-derived growth factor.
p38 mitogen-activated protein kinase (MAPK) regulates matrix metalloproteinase-1 (MMP-1) gene expression bidirectionally depending on the induction. We sought to determine whether cytokines related to the regulation of extracellular matrix could activate p38 MAPK in dermal fibroblasts. We determined p38 MAPK phosphorylation/activation in dermal fibroblasts stimulated with platelet-derived growth factor-BB (PDGF-BB), transforming growth factor-beta or interleukin-4. Induction of MMP-1 mRNA by PDGF-BB was enhanced in the presence of a specific inhibitor of p38 MAPK, suggesting that p38 MAPK would function as a negative regulator of the MMP-1 mRNA level. We then determined which isoforms of p38 MAPK expressed in dermal fibroblasts were responsible for the downregulation of the MMP-1 mRNA level. Overexpression of p38beta2, but not of p38alpha, significantly decreased PDGF-BB-induced MMP-1 promoter activity, although PDGF-BB activated signaling pathways to both p38alpha and p38beta2. Taken together, the results of this study indicate that p38beta2 can function as a negative regulator of MMP-1 induced by PDGF-BB in vitro, suggesting that activation of p38beta2 might contribute to the pathogenesis of cutaneous fibrosis.
Endo
Hideharu
H
Department of Clinical Biology of Extracellular Matrix (F7), Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Japan. chw92121@syd.odn.ne.jp
Utani
Atsushi
A
Shinkai
Hiroshi
H
D000818:Animals; D001483:Base Sequence; D000077214:Becaplermin; D002460:Cell Line; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D020574:Proto-Oncogene Proteins c-sis; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011725:Pyridines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D000077214:Becaplermin; D015847:Interleukin-4; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; C093642:SB 203580