Nitric oxide inhibits interleukin-12 p40 through p38 MAPK-mediated regulation of calmodulin and c-rel

Boddupalli, Chandra Sekhar ; Ghosh, Sudip ; Rahim, Sheikh Showkat ; Nair, Shiny ; Ehtesham, Nasreen Z. ; Hasnain, Seyed E. ; Mukhopadhyay, Sangita (2007) Nitric oxide inhibits interleukin-12 p40 through p38 MAPK-mediated regulation of calmodulin and c-rel Free Radical Biology & Medicine, 42 (5). pp. 686-697. ISSN 0891-5849

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In activated macrophages, the rel/NF-?B transcription factors are known to play important roles in interleukin-12 (IL-12) p40 regulation by nitric oxide (NO). However, the relative contributions of these factors are not well understood. Here, we describe a dominant role for c-rel involving p38 mitogen-activated protein kinase (p38 MAPK) and calmodulin (CaM) protein in NO-mediated IL-12 p40 inhibition in activated macrophages. Inhibition of NO production by aminoguanidine increased, whereas sodium nitroprusside (SNP; an exogenous NO generator) reduced, nuclear c-rel levels in LPS + IFN-γ-activated RAW 264.7 macrophages. Overexpression of c-rel but not p65 NF-kB increased IL-12 p40 during NO treatment. The p38 MAPK phosphorylation is increased by NO, and inhibition of p38 MAPK in SNP-treated macrophages by SB203580 or transient expression of a dominant-negative mutant of p38 MAPK upregulated both nuclear c-rel and IL-12 p40 levels, indicating that NO targeted the p38 MAPK pathway to inhibit c-rel and IL-12 p40. Cytoplasmic CaM level was increased by NO, and SB203580 decreased the CaM level in NO-exposed macrophages. Inhibition of CaM activity by trifluoperazine rescued the inhibitory effect of NO on c-rel and IL-12 p40. Our findings indicate that c-rel plays an important role in NO-mediated inhibition of IL-12 p40 and is regulated by p38 MAPK through CaM protein.

Item Type:Article
Source:Copyright of this article belongs to Society for Free Radical Biology and Medicine.
Keywords:Interleukin-12 p40; Nitric Oxide; p38 Mitogen-activated Protein Kinase; c-rel; Calmodulin; Free Radicals
ID Code:15258
Deposited On:13 Nov 2010 13:02
Last Modified:03 Jun 2011 05:37

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