INTERLEUKIN-1-BETA-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 cyclo oxygenase-a (Cox-a) expression with a concomitant release of prostagla ndins from glomerular mesangial cells. We reported previously that IL- 1 beta rapidly activates the c-Jun NH2-terminal/stress-activated prote in kinases (JNK/SAPK) and p38 mitogen-activated protein kinase (MAPK) and also induces Cox-a expression and prostaglandin E-2 (PGE(2)) produ ction. The current study demonstrates that overexpression of the domin ant negative form of JNK1 or p54 JNK2/SAPK beta reduces Cox-a expressi on and PGE(2) production stimulated by IL-1 beta. Similarly, overexpre ssion of the kinase-dead form of p38 MAPK also inhibits IL-1 beta-indu ced Cox-a expression and PGE(2) production. These results suggest that activation of both JMK/SAPK and p38 MAPK is required for Cox-a expres sion after IL-1 beta activation. Furthermore, our experiments confirm that IL-1 beta activates MAP kinase kinase-4 (MKK4)/SEK1, MKK3, and MK K6 in renal mesangial cells. Overexpression of the dominant negative f orm of MKK4/SEK1 decreases IL-1 beta- induced Cox-2 expression with in hibition of both JNK/SAPK and p38 MAPK phosphorylation. Overexpression of the kinase-dead form of MKK3 or MKK6 demonstrated that either of t hese two mutant kinases inhibited IL-1 beta-induced p38 MAPK phosphory lation and Cox-a expression but not JNK/SAPK phosphorylation and activ ation. This study suggests that the activation of both JNK/SAPK and p3 8 MAPK signaling cascades is required for IL-1 beta-induced Cox-a expr ession and PGE(2) synthesis.