Expression of mitogen-inducible cyclooxygenase induced by lipopolysaccharide - Mediation through both mitogen-activated protein kinase and NF-kappa B signaling pathways in macrophages

被引:229
作者
Hwang, D
Jang, BC
Yu, G
Boudreau, M
机构
[1] Pennington Biomed. Research Center, Louisiana State University, Baton Rouge
[2] Pennington Biomed. Research Center, Louisiana State University, Baton Rouge, LA 70808
关键词
cyclooxygenase; mitogen-activated protein kinases; lipopolysaccharide; protein tyrosine kinase inhibitors; macrophages; NF-kappa B;
D O I
10.1016/S0006-2952(97)00154-8
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The mitogen inducible cyclooxygenase (COX-2) is selectively expressed in lipopolysaccharide (LPS)-stimulated macrophages. However, the signaling pathways that lead to the expression of COX-2 in LPS-stimulated macrophages are not well understood. LPS activates members of mitogen-activated protein kinases (MAPKs) and NF-kappa B transcription factor in macrophages. We have shown that protein tyrosine kinase (PTK) inhibitors suppress the LPS induced expression of COX-2 in macrophages (Chanmugam et al., J Biol Chem 270: 5418-5426, 1995). These PTK inhibitors also inhibit LPS-induced activation of MAPKs. Thus, in the present study, we determined whether the activation of MAPKs and NF-kappa B is necessary for the signaling pathway for the LPS-induced expression of COX-2 in the murine macrophage cell line RAW 264.7. The findings demonstrated that inhibition of extracellular signal-regulated protein kinases 1 and 2 (ERK-1 and -2) by the selective inhibitor PD98059 or inhibition of P38 by the specific inhibitor SB203580 results in partial suppression of COX-2 expression. However, activation of MAPKs by phorbol 12-myristate 13-acetate, H2O2, sorbitol, sodium vanadate, or a combination of these agents failed to induce the expression of COX-2. Inhibitors of NF-kappa B suppressed COX 2 expression without affecting tyrosine phosphorylation of MAPKs. The PTK inhibitors that suppressed the activation of MAPKs and COX-2 expression also inhibited the degradation of I kappa B-alpha. Together, these results indicate that the activation of NF-kappa B is required to induce the expression of COX-2 in LPS-stimulated RAW 264.7 cells. Inhibition of ERK-1 and 2 or P38 results in partial suppression of COX-2 expression. However, the activation of MAPKs alone is not sufficient to induce the expression of COX-2 in these cells. (C) 1997 Elsevier Science Inc.
引用
收藏
页码:87 / 96
页数:10
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