EXPRESSION OF MITOGEN-INDUCIBLE CYCLOOXYGENASE INDUCED BY LIPOPOLYSACCHARIDE - MEDIATION THROUGH BOTH MITOGEN-ACTIVATED PROTEIN-KINASE AND NF-KAPPA-B SIGNALING PATHWAYS IN MACROPHAGES

The mitogen inducible cyclooxygenase (COX-2) is selectively expressed in lipopolysaccharide (LPS)-stimulated macrophages. However, the signa ling pathways that lead to the expression of COX-2 in LPS-stimulated m acrophages are not well understood. LPS activates members of mitogen-a ctivated protein kinases (MAPKs) and NF-kappa B transcription factor i n macrophages. We have shown that protein tyrosine kinase (PTK) inhibi tors suppress the LPS induced expression of COX-2 in macrophages (Chan mugam et al., J Biol Chem 270: 5418-5426, 1995). These PTK inhibitors also inhibit LPS-induced activation of MAPKs. Thus, in the present stu dy, we determined whether the activation of MAPKs and NF-kappa B is ne cessary for the signaling pathway for the LPS-induced expression of CO X-2 in the murine macrophage cell line RAW 264.7. The findings demonst rated that inhibition of extracellular signal-regulated protein kinase s 1 and 2 (ERK-1 and -2) by the selective inhibitor PD98059 or inhibit ion of P38 by the specific inhibitor SB203580 results in partial suppr ession of COX-2 expression. However, activation of MAPKs by phorbol 12 -myristate 13-acetate, H2O2, sorbitol, sodium vanadate, or a combinati on of these agents failed to induce the expression of COX-2. Inhibitor s of NF-kappa B suppressed COX 2 expression without affecting tyrosine phosphorylation of MAPKs. The PTK inhibitors that suppressed the acti vation 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-st imulated RAW 264.7 cells. Inhibition of ERK-1 and 2 or P38 results in partial suppression of COX-2 expression. However, the activation of MA PKs alone is not sufficient to induce the expression of COX-2 in these cells. (C) 1997 Elsevier Science Inc.