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

Journal of Leukocyte Biology

Chien-Huang Lin⁵  Chia-Kai Chang²  Chuang-Ye Hong⁴  Bing-Chang Chen¹  Ming-Jen Hsu⁶  Mei-Chieh Chen⁷  Hon-Ping Ma³ 

[1] School of Respiratory Therapy, College of Medicine, Taipei Medical University, School of Respiratory Therapy, College of Medicine, Taipei Medical University, School of Respiratory Therapy, College of Medicine, Taipei Medical University,;Graduate Institute of Medical Sciences, Departments of Graduate Institute of Medical Sciences, Departments of Graduate Institute of Medical Sciences, Departments of;Taipei Medical University-Shuang Ho Hospital, Taipei County, and Taipei Medical University-Shuang Ho Hospital, Taipei County, and Taipei Medical University-Shuang Ho Hospital, Taipei County, and;Taipei Medical University-Wang Fang Hospital, Taipei, Taiwan Taipei Medical University-Wang Fang Hospital, Taipei, Taiwan Taipei Medical University-Wang Fang Hospital, Taipei, Taiwan;Graduate Institute of Medical Sciences, Departments of Taipei Medical University-Shuang Ho Hospital, Taipei County, and Taipei Medical University-Wang Fang Hospital, Taipei, Taiwan Graduate Institute of Medical Sciences, Departments of Graduate Institute of Medical Sciences, Departments of Taipei Medical University-Shuang Ho Hospital, Taipei County, and Taipei Medical University-Wang Fang Hospital, Taipei, Taiwan Taipei Medical University-Shuang Ho Hospital, Taipei County, and Graduate Institute of Medical Sciences, Departments of Taipei Medical University-Shuang Ho Hospital, Taipei County, and Taipei Medical University-Wang Fang Hospital, Taipei, Taiwan Taipei Medical University-Wang Fang Hospital, Taipei, Taiwan Graduate Institute of Medical Sciences, Departments of Taipei Medical University-Shuang Ho Hospital, Taipei County, and Taipei Medical University-Wang Fang Hospital, Taipei, Taiwan;Graduate Institute of Medical Sciences, Departments of Pharmacology and Graduate Institute of Medical Sciences, Departments of Graduate Institute of Medical Sciences, Departments of Pharmacology and Pharmacology and Graduate Institute of Medical Sciences, Departments of Pharmacology and;Microbiology and Immunology, and Microbiology and Immunology, and Microbiology and Immunology, and

关键词: inflammation;    transcription factors;    signal transduction;    monocytes/macrophages;    Toll-like receptor;   

DOI  :  10.1189/jlb.1009668

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

In this study, we investigated the role of ASK1 in PGN-induced C/EBPβ 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/EBPβ 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/EBPβ cascade was activated in human peripheral mononuclear cells exposure to PGN. The TLR2 agonist Pam3CSK4 was also shown to induce ASK1 Ser967 dephosphorylation, JNK and c-jun phosphorylation, C/EBPβ 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/EBPβ cascade and subsequent COX-2 expression in RAW 264.7 macrophages.

【 授权许可】

Unknown