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J Biol Chem, Vol. 274, Issue 51, 36200-36206, December 17, 1999

Both p38^MAPK and JNK/SAPK Pathways Are Important for Induction of Nitric-oxide Synthase by Interleukin-1 in Rat Glomerular Mesangial Cells^*

Zhonghong Guan, ShaAvhree Y. Buckman, Lisa D. Springer, and Aubrey R. Morrison^§

From the Department of Medicine and Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

Interleukin 1 (IL-1) 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 SAPK/JNK2 significantly reduces the iNOS protein expression and NO production induced by IL-1. Similarly, overexpression of the kinase-dead mutant form of p38^MAPK also inhibits IL-1-induced iNOS expression and NO production. In previous studies we demonstrated that IL-1 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-1. Overexpression of the dominant negative form of MKK4/SEK1 decreases IL-1-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-1-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-1, iNOS expression was not enhanced. This study suggests that the activation of both SAPK/JNK and p38^MAPK signaling cascades are necessary for the IL-1-induced expression of iNOS and production of NO in renal mesangial cells.

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^* This work was supported in part by United States Public Health Award DK 50606.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a Missouri Kidney Foundation award.

^§ To whom correspondence should be addressed: Barnes Jewish Hospital, Renal Division, 216 S. Kings Highway, Box 8305, St. Louis, MO 63110. Tel.: 314-454-8495; Fax: 314-454-8430; E-mail: morrison@ molecool.wustl.edu.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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