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(Received for publication, September 17, 1996, and in revised form, January 17, 1997)
From the Department of Molecular Biology & Pharmacology and
Medicine, Washington University School of Medicine,
St. Louis, Missouri 63110
The inflammatory cytokine interleukin 1
Volume 272, Number 12,
Issue of March 21, 1997
pp. 8083-8089
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
(IL-1) induces both cyclooxygenase-2 (Cox-2) and the inducible
nitric-oxide synthase (iNOS) with increases in the release of
prostaglandins (PGs) and nitric oxide (NO) from glomerular mesangial
cells. However, the intracellular signaling mechanisms by which IL-1
induces iNOS and Cox-2 expression is obscure. Our current studies
demonstrate that IL-1 produces a rapid increase in p38
mitogen-activated protein kinase (MAPK) phosphorylation and activation.
Serum starvation and SC68376, a drug which selectively inhibits p38
MAPK in mesangial cells, were used to investigate whether p38 MAPK
contributes to the signaling mechanism of IL-1 induction of NO and
PG synthesis. Serum starvation and SC68376 selectively inhibited
IL-1-induced activation of p38 MAPK. Both SC68376 and serum
starvation enhanced NO biosynthesis by increasing iNOS mRNA
expression, protein expression, and nitrite production. In contrast,
both SC68376 and serum starvation suppressed PG release by inhibiting
Cox-2 mRNA, protein expression, and PGE2
synthesis. These data demonstrate that IL-1 phosphorylates and
activates p38 MAPK in mesangial cells. The activation of p38 MAPK may
provide a crucial signaling mechanism, which mediates the up-regulation
of PG synthesis and the down-regulation of NO biosynthesis induced by
IL-1.
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C. M. Larsen, K. A. W. Wadt, L. F. Juhl, H. U. Andersen, A. E. Karlsen, M. S.-S. Su, K. Seedorf, L. Shapiro, C. A. Dinarello, and T. Mandrup-Poulsen Interleukin-1beta -induced Rat Pancreatic Islet Nitric Oxide Synthesis Requires Both the p38 and Extracellular Signal-regulated Kinase 1/2 Mitogen-activated Protein Kinases J. Biol. Chem., June 12, 1998; 273(24): 15294 - 15300. [Abstract] [Full Text] [PDF]
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Z. Guan, S. Y. Buckman, A. P. Pentland, D. J. Templeton, and A. R. Morrison Induction of Cyclooxygenase-2 by the Activated MEKK1 right-arrow SEK1/MKK4 right-arrow p38 Mitogen-activated Protein Kinase Pathway J. Biol. Chem., May 22, 1998; 273(21): 12901 - 12908. [Abstract] [Full Text] [PDF]
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T. Yang, I. Singh, H. Pham, D. Sun, A. Smart, J. B. Schnermann, and J. P. Briggs Regulation of cyclooxygenase expression in the kidney by dietary salt intake Am J Physiol Renal Physiol, March 1, 1998; 274(3): F481 - F489. [Abstract] [Full Text] [PDF]
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J. Da Silva, B. Pierrat, J.-L. Mary, and W. Lesslauer Blockade of p38 Mitogen-activated Protein Kinase Pathway Inhibits Inducible Nitric-oxide Synthase Expression in Mouse Astrocytes J. Biol. Chem., November 7, 1997; 272(45): 28373 - 28380. [Abstract] [Full Text] [PDF]
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K. Bellmann, V. Burkart, J. Bruckhoff, H. Kolb, and J. Landry p38-dependent Enhancement of Cytokine-induced Nitric-oxide Synthase Gene Expression by Heat Shock Protein 70 J. Biol. Chem., June 9, 2000; 275(24): 18172 - 18179. [Abstract] [Full Text] [PDF]
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