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

The inflammatory cytokine interleukin-1 beta (IL-1 beta) induces cyclooxygenase-a (Cox-a) expression with a concomitant release of prostaglandins from glomerular mesangial cells. We reported previously that IL-1 beta rapidly activates the c-Jun NH2-terminal/stress-activated protein kinases (JNK/SAPK) and p38 mitogen-activated protein kinase (MAPK) and also induces Cox-a expression and prostaglandin E-2 (PGE(2)) production. The current study demonstrates that overexpression of the dominant negative form of JNK1 or p54 JNK2/SAPK beta reduces Cox-a expression and PGE(2) production stimulated by IL-1 beta. Similarly, overexpression of the kinase-dead form of p38 MAPK also inhibits IL-1 beta-induced Cox-a expression and PGE(2) production. These results suggest that activation of both JMK/SAPK and p38 MAPK is required for Cox-a expression after IL-1 beta activation. Furthermore, our experiments confirm that IL-1 beta 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-1 beta- 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-1 beta-induced p38 MAPK phosphorylation and Cox-a 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-1 beta-induced Cox-a expression and PGE(2) synthesis.