Monick Martha M, Samavati Lobelia, Butler Noah S, Mohning Michael, Powers Linda S, Yarovinsky Timur, Spitz Douglas R, Hunninghake Gary W
Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, and Veterans' Administration Medical Center, Iowa City, IA 52242, USA.
J Immunol. 2003 Nov 15;171(10):5107-15. doi: 10.4049/jimmunol.171.10.5107.
A number of lung diseases, including many interstitial lung diseases and HIV infection, are associated with decreases in intracellular thiols. Altered Th1/Th2 T cell balance has also been associated with disease progression in many of the same diseases. IFN-gamma and IL-4 are critical effector cytokines of Th1 and Th2 cells, respectively. To determine the effect of thiols on the production of IFN-gamma and IL-4 by splenocytes, cells were incubated in the presence and the absence of N-acetylcysteine (NAC) and stimulated with alphaCD3 or alphaCD3 and IL-12. Augmenting intracellular soluble thiol pools ( approximately 2-fold) with 15 mM NAC blocked induction of IFN-gamma and increased production of IL-4 without causing significant changes in intracellular glutathione levels. The effect of NAC on IL-4 production was not linked to an increase in STAT6 phosphorylation, as STAT6 levels were decreased, nor did the increase in IL-4 occur with purified CD4 cells. We found that NAC increased splenocyte IL-4 production via an effect on APCs. We also found that NAC increased two IL-4 relevant transcription factors (AP-1) and NFATc. These studies suggest that increasing intracellular reduced thiol pools decreases IL-12 signaling and IFN-gamma production, while increasing IL-4 production. The sum of these effects may contribute to alterations in the balance between Th1 and Th2 responses in lung diseases associated alterations in intracellular thiol pools.
许多肺部疾病，包括许多间质性肺病和HIV感染，都与细胞内硫醇减少有关。Th1/Th2 T细胞平衡的改变也与许多相同疾病的疾病进展有关。IFN-γ和IL-4分别是Th1和Th2细胞的关键效应细胞因子。为了确定硫醇对脾细胞产生IFN-γ和IL-4的影响，细胞在有和没有N-乙酰半胱氨酸（NAC）的情况下孵育，并用αCD3或αCD3和IL-12刺激。用15 mM NAC增加细胞内可溶性硫醇池（约2倍）可阻断IFN-γ的诱导并增加IL-4的产生，而不会引起细胞内谷胱甘肽水平的显著变化。NAC对IL-4产生的影响与STAT6磷酸化的增加无关，因为STAT6水平降低，纯化的CD4细胞也未出现IL-4的增加。我们发现NAC通过对APC的作用增加脾细胞IL-4的产生。我们还发现NAC增加了两种与IL-4相关的转录因子（AP-1）和NFATc。这些研究表明，增加细胞内还原型硫醇池可减少IL-12信号传导和IFN-γ的产生，同时增加IL-4的产生。这些作用的总和可能导致与细胞内硫醇池改变相关的肺部疾病中Th1和Th2反应平衡的改变。
