Nitric oxide inhibits interleukin-12 p40 through p38 MAPK-mediated regulation of calmodulin and c-rel
Nitric oxide inhibits interleukin-12 p40 through p38 MAPK-mediated regulation of calmodulin and c-rel
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DOI：
10.1016/j.freeradbiomed.2006.12.014
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发表时间：
2007-03-01
影响因子：
7.4
通讯作者：
Mukhopadhyay, Sangita
中科院分区：
文献类型：
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作者：
Boddupalli, Chandra Sekhar;Ghosh, Sudip;Mukhopadhyay, Sangita
在活化的巨噬细胞中，已知rel/NF-κ B转录因子在一氧化氮（NO）调节白细胞介素-12（IL-12）p40中起重要作用。然而，这些因素的相对贡献并没有得到很好的理解。在这里，我们描述了一个占主导地位的作用，c-rel涉及p38丝裂原活化蛋白激酶（p38 MAPK）和钙调蛋白（CaM）蛋白在NO介导的IL-12 p40抑制活化的巨噬细胞。在LPS+ IFN-γ激活的RAW 264.7巨噬细胞中，氨基胍对NO产生的抑制作用增加，而硝普钠（SNP;外源性NO发生器）降低了核c-rel水平。在NO处理期间，c-rel而非p65 NF-κ B的过表达增加了IL-12 p40。p38 MAPK磷酸化被NO增加，并且在SNP处理的巨噬细胞中通过SB 203580或p38 MAPK的显性负突变体的瞬时表达抑制p38 MAPK上调核c-rel和IL-12 p40水平，表明NO靶向p38 MAPK通路以抑制c-rel和IL-12 p40。NO可使巨噬细胞胞浆CaM水平升高，SB 203580可使其胞浆CaM水平降低。通过三氟拉嗪抑制CaM活性可挽救NO对c-rel和IL-12 p40的抑制作用。我们的研究结果表明，c-rel在NO介导的IL-12 p40抑制中起重要作用，并通过CaM蛋白由p38 MAPK调节。(c)2006年爱思唯尔公司All rights reserved.
In activated macrophages, the rel/NF-kappa 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-gamma-activated RAW 264.7 macrophages. Overexpression of c-rel but not p65 NF-kappa B 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. (c) 2006 Elsevier Inc. All rights reserved.