Intracellular Thiols Contribute to Th2 Function via a Positive Role in IL-4 Production

Abstract

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-γ and IL-4 are critical effector cytokines of Th1 and Th2 cells, respectively. To determine the effect of thiols on the production of IFN-γ and IL-4 by splenocytes, cells were incubated in the presence and the absence of N-acetylcysteine (NAC) and stimulated with αCD3 or αCD3 and IL-12. Augmenting intracellular soluble thiol pools (∼2-fold) with 15 mM NAC blocked induction of IFN-γ 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-γ 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.

N-acetyl-cysteine accelerates transfer of diabetes into non-obese diabetic scid mice

“…However, others reported that cytokine production by splenocytes of BALB/c mice was skewed towards a Th2 pattern when NAC was added in vitro [19]. In this study, we have shown that NAC enhances Th1 responses of NOD splenocytes in vitro and in vivo.…”

Ncf1-Associated Reduced Oxidative Burst Promotes IL-33R+ T Cell-Mediated Adjuvant-Free Arthritis in Mice

“…Some groups reported that low intracellular glutathione levels in murine APC or oxidative stress in human PBMC, respectively, promote the differentiation toward a Th2 phenotype (44,45). However, there are also reports suggesting that augmenting the intracellular thiol pool in mouse splenocytes with N-acetylcysteine blocked the induction of IFN-␥ and instead promoted IL-4 production and Th2 differentiation (46). This is consistent with our results showing that a more reduced milieu in APC due to the Ncf1 mutation mediated lack of ROS induces a more pronounced Th2 environment.…”

The Role of CD4 T Cells in the Pathogenesis of Murine AIDS

“…It has generally been accepted that a Th1/Th2 imbalance underlies various immune diseases. In HIV-infected patients and LP-BM5-infected mice, T-cell proliferation and Th1 cytokine (IL-2 and IFN-␥) production have been reported to decline, while Th2 cytokine (IL-4, IL-5, IL-6, and IL-10) and immunoglobulin production increase (4,5,10,12,26,34,45,49,57).…”

“…Th1 cells are involved in the pathogenesis of several organ-specific autoimmune disorders. In contrast, allergen-specific Th2 responses may be critical for atopic disorders in genetically susceptible individuals, and skewing to a Th2 response in certain infections diseases, such as leishmaniasis, leprosy, and others, results in a lack of clearance of the causative microbe and consequently in enhanced microbial and/or immunological pathology (4,34,45,57).…”

“…There is some evidence suggesting that a Th2-type cytokine response is often associated with progression to AIDS in HIV-positive individuals (4,5,10,12,34,49,57). Thus, it seemed important to study here the question of whether the Th1 and Th2 subsets were differentially able to mediate LP-BM5-induced MAIDS pathogenesis.…”