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-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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylcysteine / pharmacology
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Active Transport, Cell Nucleus / drug effects
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Active Transport, Cell Nucleus / immunology
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Adjuvants, Immunologic / physiology*
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Animals
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Antigen-Presenting Cells / immunology
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CD3 Complex / metabolism
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CD3 Complex / pharmacology
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Cell Nucleus / immunology
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Cell Nucleus / metabolism
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Cells, Cultured
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Cytokines / biosynthesis
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DNA-Binding Proteins / metabolism
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Down-Regulation / drug effects
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Down-Regulation / immunology
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Drug Combinations
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Female
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / biosynthesis
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Interleukin-12 / antagonists & inhibitors
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Interleukin-12 / pharmacology
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Interleukin-4 / biosynthesis*
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Interleukin-4 / metabolism
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Interphase / immunology
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Intracellular Fluid / physiology*
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Transgenic
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NFATC Transcription Factors
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Nuclear Proteins*
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STAT6 Transcription Factor
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Solubility
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Spleen / cytology
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Spleen / immunology
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Sulfhydryl Compounds / physiology*
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Th2 Cells / immunology*
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Th2 Cells / metabolism*
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Th2 Cells / physiology
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / metabolism
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Transcription Factor AP-1 / metabolism
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Transcription Factors / metabolism
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Up-Regulation / drug effects
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Up-Regulation / immunology
Substances
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Adjuvants, Immunologic
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CD3 Complex
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Cytokines
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DNA-Binding Proteins
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Drug Combinations
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NFATC Transcription Factors
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Nuclear Proteins
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STAT6 Transcription Factor
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Stat6 protein, mouse
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Sulfhydryl Compounds
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Trans-Activators
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Transcription Factor AP-1
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Transcription Factors
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Interleukin-12
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Interleukin-4
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Interferon-gamma
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Acetylcysteine