| Title | Peptidoglycan induces cyclooxygense-2 expression in macrophages by activating the neutral sphingomyelinase-ceramide pathway. | | Author(s) | Chen BC, Chang HM, Hsu MJ, Shih CM, Chiu YH, Chiu WT, Lin CH | | Institution | Taipei Medical University, Taiwan. | | Source | J Biol Chem 2009 Jun 15. | | Abstract | The sphingomyelin signal transduction pathway is known to play a role in mediating the action of various cytokines. Herein, we examined the role of neutral sphingomyelinase (nSMase)/ceramide in peptidoglycan (PGN)-induced NF-kappaB activation and cyclooxygenase-2 (COX-2) expression in macrophages. PGN-induced COX-2 expression was attenuated by an nSMase inhibitor (3-O-methyl-sphingomyeline, 3-OMS) and ceramidase, but not by an acidic sphingomyelinase (aSMase) inhibitor (imipramine). C2-ceramide, bacterial SMase (which mimics cellular SMase activity), and a ceramidase inhibitor (N-oleoyl-ethanolamine, NOE) individually had no effect on COX-2 expression; however, they markedly enhanced PGN-induced COX-2 expression. PGN activated nSMase, but not aSMase, resulting in increased ceramide generation. PGN-induced nSMase activation and ceramide formation were inhibited by 3-OMS, but not by imipramine. PGN-induced COX-2 expression was inhibited by a p38 MAPK inhibitor (SB 203580) and dominant negative mutants (DNs) of MKK3, MKK6, and p38 MAPKalpha. 3-OMS selectively inhibited PGN-induced p38 MAPK and MKK3/6 activation, but not JNK or ERK1/2. C2-ceramide, bacterial SMase, and NOE all induced p38 MAPK or MKK3/6 activation. The PGN-mediated increases in kappaB-luciferase activity were also inhibited by 3-OMS and the p38 MAPKalphaDN, but not by imipramine. Furthermore, C2-ceramide caused an increase in kappaB-luciferase activity. Our data demonstrate for the first time that PGN activates the nSMase/ceramide pathway to induce MKK3/6/p38 MAPK activation, which in turn initiates NF-kappaB activation, and ultimately induces COX-2 expression in macrophages. The nSMase/ceramide pathway is required but might not be sufficient for COX-2 expression induced by PGN. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19531467 |
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