IL-4 gene expression up-regulated by mercury in rat mast cells: a role of oxidant stress in IL-4 transcription.
In the Brown Norway (BN) rat, chemical compounds [mercuric chloride (HgCl2), D-penicillamine or gold salts] induce a T(h)2-dominated autoimmune syndrome with tissue injury in the form of a vasculitis and arthritis. An early phase of vasculitis in the model occurs within 24 h of an injection of HgCl2, is alphabeta T cell independent and involves the mast cell. In addition, HgCl2 induces IL-4 mRNA in mast cells from BN rats. Our recent work has demonstrated that the balance of oxidative/antioxidative influences plays an important role in the modulation of mast cell function (degranulation) in chemically induced autoimmunity. The aim of this study was to determine, in mast cells, whether oxidative status influences IL-4 transcription and translation, which is required for the development of a T(h)2 response. Exposure of the mast cell line RBL-2H3 to HgCl2 enhanced both IL-4 mRNA and its promoter activity. Oxidative stress by hydrogen peroxide mimicked the effects of HgCl2 in enhancing IL-4 promoter activity. The enhancement of IL-4 gene expression by HgCl2 was significantly reduced by antioxidants (both sulphydryl and non-sulphydryl containing). The same pattern of regulation was also observed on IL-4 protein expression in the mast cells. These data suggest a novel mechanism of IL-4 transcriptional up-regulation by oxidative stress. Our results provide evidence to support our hypothesis that alterations in intracellular reactive oxygen species production modulate both IL-4 gene expression and mast cell function.
Division of Renal Medicine, St George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK.
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Wu
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Turner
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Oliveira
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015551:Autoimmunity; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D005978:Glutathione / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics; D015471:Leukemia, Basophilic, Acute / Q000473:pathology; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D008627:Mercuric Chloride / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D051381:Rats; D011914:Rats, Inbred BN; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D018418:Th2 Cells / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000975:Antioxidants; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D015847:Interleukin-4; D008627:Mercuric Chloride; D006861:Hydrogen Peroxide; D005978:Glutathione