Interleukin-1β-induced Cyclooxygenase-2 Expression Requires Activation of Both c-Jun NH2-terminal Kinase and p38 MAPK Signal Pathways in Rat Renal Mesangial Cells

• Published in: The Journal of biological chemistry 1998-10, Vol.273 (44), p.28670-28676
• Main Authors: Guan, Zhonghong, Buckman, ShaAvhree Y., Miller, Brent W., Springer, Lisa D., Morrison, Aubrey R.
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.44.28670

The inflammatory cytokine interleukin-1β (IL-1β) induces cyclooxygenase-2 (Cox-2) expression with a concomitant release of prostaglandins from glomerular mesangial cells. We reported previously that IL-1β rapidly activates the c-Jun NH2-terminal/stress-activated protein kinases (JNK/SAPK) and p38 mitogen-activated protein kinase (MAPK) and also induces Cox-2 expression and prostaglandin E2 (PGE2) production. The current study demonstrates that overexpression of the dominant negative form of JNK1 or p54 JNK2/SAPKβ reduces Cox-2 expression and PGE2 production stimulated by IL-1β. Similarly, overexpression of the kinase-dead form of p38 MAPK also inhibits IL-1β-induced Cox-2 expression and PGE2production. These results suggest that activation of both JNK/SAPK and p38 MAPK is required for Cox-2 expression after IL-1β activation. Furthermore, our experiments confirm that IL-1β activates MAP kinase kinase-4 (MKK4)/SEK1, MKK3, and MKK6 in renal mesangial cells. Overexpression of the dominant negative form of MKK4/SEK1 decreases IL-1β- induced Cox-2 expression with inhibition of both JNK/SAPK and p38 MAPK phosphorylation. Overexpression of the kinase-dead form of MKK3 or MKK6 demonstrated that either of these two mutant kinases inhibited IL-1β-induced p38 MAPK phosphorylation and Cox-2 expression but not JNK/SAPK phosphorylation and activation. This study suggests that the activation of both JNK/SAPK and p38 MAPK signaling cascades is required for IL-1β-induced Cox-2 expression and PGE2synthesis.