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

• Published in: Biochemical pharmacology 1997-07, Vol.54 (1), p.87-96
• Main Authors: HWANG, D, JANG, B. C, YU, G, BOUDREAU, M
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell physiology; Fundamental and applied biological sciences. Psychology; Molecular and cellular biology; Signal transduction
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(97)00154-8

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. 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, H sub(2)O sub(2), 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.