TY - JOUR
T1 - 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
AU - Guan, Zhonghong
AU - Buckman, Sha Avhree Y.
AU - Miller, Brent W.
AU - Springer, Lisa D.
AU - Morrison, Aubrey R.
PY - 1998/10/30
Y1 - 1998/10/30
N2 - 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 kinasedead form of p38 MAPK also inhibits IL-1β-induced Cox-2 expression and PGE2 production. 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 NK/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 PGE2 synthesis.
AB - 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 kinasedead form of p38 MAPK also inhibits IL-1β-induced Cox-2 expression and PGE2 production. 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 NK/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 PGE2 synthesis.
UR - http://www.scopus.com/inward/record.url?scp=0032582347&partnerID=8YFLogxK
U2 - 10.1074/jbc.273.44.28670
DO - 10.1074/jbc.273.44.28670
M3 - Article
C2 - 9786861
AN - SCOPUS:0032582347
SN - 0021-9258
VL - 273
SP - 28670
EP - 28676
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 44
ER -