Both p38α(MAPK) and JNK/SAPK pathways are important for induction of nitric-oxide synthase by interleukin-1β in rat glomerular mesangial cells

Zhonghong Guan, Sha Avhree Y. Buckman, Lisa D. Springer, Aubrey R. Morrison

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

Interleukin 1β (IL-1β) induces expression of the inducible nitric- oxide synthase (iNOS) with concomitant release of nitric oxide (NO) from glomerular mesangial cells. These events are preceded by activation of the c- Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38(MAPK). Our current study demonstrates that overexpression of the dominant negative form of JNK1 or p54 SAPKβ/JNK2 significantly reduces the iNOS protein expression and NO production induced by IL-1β. Similarly, overexpression of the kinase-dead mutant form of p38α(MAPK) also inhibits IL-1β-induced iNOS expression and NO production. In previous studies we demonstrated that IL-1β can activate MKK4/SEK1, MKK3, and MKK6 in renal mesangial cells; therefore, we examined the role of these MAPK kinases in the modulation of iNOS induced by IL-1β. Overexpression of the dominant negative form of MKK4/SEK1 decreases IL-1β-induced iNOS expression and NO production with inhibition of both SAPK/JNK and p38(MAPK) phosphorylation. Overexpression of the kinase-dead mutant form of MKK3 or MKK6 demonstrated that either of these two mutant kinase inhibited IL-1β-induced p38(MAPK) (but not JNK/SAPK) phosphorylation and iNOS expression. Interestingly overexpression of wild type MKK3/6 was associated with phosphorylation of p38(MAPK); however, in the absence of IL-1β, iNOS expression was not enhanced. This study suggests that the activation of both SAPK/JNK and p38α(MAPK) signaling cascades are necessary for the IL-1β-induced expression of iNOS and production of NO in renal mesangial cells.

Original languageEnglish
Pages (from-to)36200-36206
Number of pages7
JournalJournal of Biological Chemistry
Volume274
Issue number51
DOIs
StatePublished - Dec 17 1999

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