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p38 mitogen-activated protein kinase down-regulates nitric oxide and up-regulates prostaglandin E2 biosynthesis
Z Guan1, L D Baier, A R Morrison
1Department of Molecular Biology & Pharmacology and Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Abstract:
The inflammatory cytokine interleukin 1beta (IL-1beta) 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-1beta induces iNOS and Cox-2 expression is obscure. Our current studies demonstrate that IL-1beta 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-1beta induction of NO and PG synthesis. Serum starvation and SC68376 selectively inhibited IL-1beta-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-1beta 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-1beta.
Insights
Interleukin 1beta (IL-1beta) activates p38 MAPK in kidney mesangial cells. This activation up-regulates prostaglandin synthesis while down-regulating nitric oxide production, revealing key signaling pathways.
Area of Science:
- Nephrology
- Molecular Biology
- Inflammation Research
Background:
- Interleukin 1beta (IL-1beta) is an inflammatory cytokine.
- IL-1beta stimulates glomerular mesangial cells to release prostaglandins (PGs) and nitric oxide (NO).
- The intracellular signaling pathways mediating IL-1beta's effects on cyclooxygenase-2 (Cox-2) and inducible nitric-oxide synthase (iNOS) are not fully understood.
Purpose of the Study:
- To investigate the role of p38 mitogen-activated protein kinase (MAPK) in IL-1beta-induced signaling.
- To determine if p38 MAPK activation mediates the effects of IL-1beta on NO and PG synthesis in mesangial cells.
Main Methods:
- Mesangial cells were treated with IL-1beta.
- p38 MAPK activation was assessed.
- Cells were subjected to serum starvation or treated with SC68376, a p38 MAPK inhibitor.
- iNOS and Cox-2 mRNA and protein expression, nitrite production (NO marker), and PGE2 synthesis (PG marker) were measured.
Main Results:
- IL-1beta rapidly increased p38 MAPK phosphorylation and activation in mesangial cells.
- Inhibition of p38 MAPK (via serum starvation or SC68376) enhanced NO biosynthesis by up-regulating iNOS.
- Inhibition of p38 MAPK suppressed PG release by down-regulating Cox-2 and PGE2 synthesis.
Conclusions:
- IL-1beta activates p38 MAPK in glomerular mesangial cells.
- p38 MAPK signaling is crucial for IL-1beta-induced prostaglandin synthesis.
- p38 MAPK signaling mediates the down-regulation of nitric oxide biosynthesis induced by IL-1beta.