Nitric oxide contributes to the development of a post-injury Th2 T-Cell phenotype and immune dysfunction
Nitric oxide contributes to the development of a post-injury Th2 T-Cell phenotype and immune dysfunction
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DOI：
10.1002/jcp.20677
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发表时间：
2006-08-01
影响因子：
5.6
通讯作者：
Schwacha, Martin G.
中科院分区：
文献类型：
--
作者：
Daniel, Tanjanika;Alexander, Michelle;Schwacha, Martin G.
严重损伤诱导免疫功能障碍，导致对机会性感染的易感性增加。本实验室先前的研究表明，烧伤后免疫抑制是由一氧化氮（NO）介导的，由于巨噬细胞诱导型一氧化氮合酶（iNOS）的表达增加。相反，其他人认为，损伤导致Th 1和Th 2免疫应答调节的表型失衡。目前尚不清楚这些明显不同的免疫抑制介质是否相互关联。为了研究这一点，使C57 BL/6小鼠经受严重烧伤，7天后分离脾细胞并用抗CD 3刺激。烧伤诱导NO介导的增殖反应的抑制，在NOS抑制剂L-单甲基-L-精氨酸的存在下被逆转，随后通过添加NO供体S-亚硝基-N-乙酰基-青霉胺（SNAP）来模拟。SNAP还剂量依赖性地抑制IFN-γ和IL-2（Th 1）的产生，但不抑制IL-4和IL-10（Th 2）的产生。将SNAP添加到培养物中延迟24小时防止了IFN-γ产生的抑制。免疫表型中的Th 2漂移与cGMP和细胞凋亡无关。此外，SNAP的细胞培养物也诱导细胞凋亡，减弱线粒体氧化代谢和诱导线粒体膜去极化。然而，NO的这些有害细胞效应仅在超生理浓度（> 250 μ M）下观察到。总之，这些发现支持了这样的概念，即NO通过对Th 1 T细胞的选择性作用诱导细胞介导的免疫应答的抑制，从而促进Th 2应答。
Severe injury induces immune dysfunction resulting in increased susceptibility to opportunistic infections. Previous studies from our laboratory have demonstrated that post-burn immunosuppression is mediated by nitric oxide (NO) due to the increased expression of macrophage inducible nitric oxide synthase (iNOS). In contrast, others suggest that injury causes a phenotypic imbalance in the regulation of Th1 - and Th2 immune responses. It is unclear whether or not these apparently divergent mediators of immunosuppression are interrelated. To study this, C57BL/6 mice were subjected to major burn injury and splenocytes were isolated 7 days later and stimulated with antiCD3. Burn injury induced NO-mediated suppression of proliferative responses that was reversed in the presence of the NOS inhibitor L-monomethyl-L-arginine and subsequently mimicked by the addition of the NO donor, S-nitroso-N-acetyl-penicillamine (SNAP). SNAP also dose-dependently suppressed IFN-gamma and IL-2 (Th1, but not IL-4 and IL-10 (Th2) production. Delaying the addition of SNAP to the cultures by 24 h prevented the suppression of IFN-gamma production. The Th2 shift in immune phenotype was independent of cGMP and apoptosis. The addition of SNAP to cell cultures also induced apoptosis, attenuated mitochondrial oxidative metabolism and induced mitochondrial membrane depolarization. However, these detrimental cellular effects of NO were observed only at supra-physiologic concentrations (> 250 mu M). In conclusion, these findings support the concept that NO induces suppression of cell-mediated immune responses by selective action on Th1 T cells, thereby promoting a Th2 response.