Apoptosis signal-regulating kinase 1 in peptidoglycan-induced COX-2 expression in macrophages

作者：Hsu Ming Jen; Chang Chia Kai; Chen Mei Chieh; Chen Bing Chang; Ma Hon Ping; Hong Chuang Ye; Lin Chien Huang^*

来源：Journal of Leukocyte Biology, 2010, 87(6): 1069-1082.

DOI：10.1189/jlb.1009668

• inflammation
• transcription factors
• signal transduction
• monocytes/macrophages
• Toll-like receptor

In this study, we investigated the role of ASK1 in PGN-induced C/EBP beta activation and COX-2 expression in RAW 264.7 macrophages. The PGN-induced COX-2 expression was attenuated by the DNs of ASK1, JNK1, JNK2, a JNK inhibitor (SP600125), and an AP-1 inhibitor (curcumin). PGN caused ASK1 dephosphorylation time-dependently at Ser967, dissociation from the ASK1-14-3-3 complex, and subsequent ASK1 activation. In addition, PGN activated PP2A and suppression of PP2A by okadaic acid markedly inhibited PGN-induced ASK1 Ser967 dephosphorylation and COX-2 expression. PGN induced the activation of the JNK-AP-1 signaling cascade downstream of ASK1. PGN-increased C/EBP beta expression and DNA-binding activity were inhibited by the ASK1-JNK-AP-1 signaling blockade. COX-2 promoter luciferase activity induced by PGN was attenuated in cells transfected with the COX-2 reporter construct possessing the C/EBP-binding site mutation. In addition, the ASK1-JNK-AP-1-C/EBP beta cascade was activated in human peripheral mononuclear cells exposure to PGN. The TLR2 agonist Pam(3)CSK(4) was also shown to induce ASK1 Ser967 dephosphorylation, JNK and c-jun phosphorylation, C/EBP beta activation, and COX-2 expression in RAW 264.7 macrophages. PGN-induced COX-2 promoter luciferase activity was prevented by selective inhibition of TLR2 and c-Jun in RAW 264.7 macrophages. Our data demonstrate that PGN might activate the TLR2-mediated PP2A-ASK1-JNK-AP-1-C/EBP beta cascade and subsequent COX-2 expression in RAW 264.7 macrophages. J. Leukoc. Biol. 87: 1069-1082; 2010.

• 出版日期2010-6
• 单位河北医科大学