title: 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-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.
authors: 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. martha-monick@uiowa.edu
authors: Martha M
authors: MM
authors: Monick
authors: Lobelia
authors: L
authors: Samavati
authors: Noah S
authors: NS
authors: Butler
authors: Michael
authors: M
authors: Mohning
authors: Linda S
authors: LS
authors: Powers
authors: Timur
authors: T
authors: Yarovinsky
authors: Douglas R
authors: DR
authors: Spitz
authors: Gary W
authors: GW
authors: Hunninghake
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D017252:CD3 Complex / Q000378:metabolism / Q000494:pharmacology; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004338:Drug Combinations; D005260:Female; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000378:metabolism; D007399:Interphase / Q000276:immunology; D007424:Intracellular Fluid / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D050800:STAT6 Transcription Factor; D012995:Solubility; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013438:Sulfhydryl Compounds / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D017252:CD3 Complex; D016207:Cytokines; D004268:DNA-Binding Proteins; D004338:Drug Combinations; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D013438:Sulfhydryl Compounds; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D000111:Acetylcysteine