Lipopolysaccharide induces matrix metalloproteinase-9 expression via a mitochondrial reactive oxygen species-p38 kinase-activator protein-1 pathway in Raw 264.7 cells.
We have identified a novel signaling pathway that leads to expression of matrix metalloproteinase-9 (MMP-9) in murine macrophages in response to the bacterial endotoxin, LPS. We showed that p38 kinase was essential for this induction and observed that LPS-induced MMP-9 expression was sensitive to rottlerin, a putative protein kinase Cdelta (PKCdelta) inhibitor. However neither infection with a retrovirus expressing a dominant negative mutant of PKCdelta nor down-regulation of PKCdelta by prolonged PMA treatment affected MMP-9 expression, thus excluding involvement of PKCdelta. Interestingly, LPS-induced MMP-9 expression and p38 kinase phosphorylation were shown to be suppressed by the antioxidant N-acetylcysteine and the flavoenzyme inhibitor diphenyleneiodonium chloride, but not by pyrrolidine dithiocarbamate, an NF-kappaB inhibitor. In addition, LPS was found to induce the production of mitochondrial reactive oxygen species (ROS) and this effect was rottlerin-sensitive, suggesting an inhibitory effect of rottlerin on mitochondrial ROS. LPS-induced MMP-9 expression and p38 kinase phosphorylation were also inhibited by rotenone, a specific inhibitor of mitochondrial complex I, supporting the role of mitochondrial ROS in LPS signaling to MMP-9. Finally, we showed that the ROS-p38 kinase cascade targets the transcription factor AP-1. Taken together, our findings identify a ROS-p38 kinase-AP-1 cascade as a novel pathway mediating LPS signaling to MMP-9 expression in macrophages.
Woo
Chang-Hoon
CH
School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
Lim
Jae-Hyang
JH
Kim
Jae-Hong
JH
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002460:Cell Line; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000276:immunology; D007527:Isoenzymes / Q000502:physiology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000502:physiology; D051745:Protein Kinase C-delta; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000378:metabolism / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000502:physiology*
D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; C085746:rottlerin; C497259:Prkcd protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9