Characterization of cis‐regulatory elements conferring mercury‐induced interleukin‐4 gene expression in rat mast cells: a role for signal transducer and activator of transcription 6 and TATA box binding sites

Abstract

Summary We have previously shown that oxidative stress is involved in the pathogenesis of a mercuric chloride (HgCl2)‐induced, T helper type 2 (Th2)‐driven autoimmune syndrome in Brown Norway (BN) rats. In the context of the syndrome, the oxidative stress‐induced mast cell response seems to determine the development of the early phase of vasculitis, while oxidative stress‐mediated interleukin (IL)‐4 production may contribute to the subsequent Th2‐driven autoimmune response. However, the molecular basis of IL‐4 gene transcription induced by HgCl2 in mast cells remains unknown. In the present study, we dissect the critical regulatory mechanisms in the IL‐4 gene promoter in the rat mast cell line RBL‐2H3. Immunoprecipitation provided evidence that treatment with HgCl2 increased phosphorylation of signal transducer and activator of transcription 6 (STAT6). Transient transfection reporter analyses with a series of 5′ end deletions of the IL‐4 promoter produced evidence that STAT6 and TATA box binding sites are important in HgCl2‐induced IL‐4 gene expression. Subsequent elimination of one or both sites by site‐directed mutagenesis significantly inhibited IL‐4 promoter activity. Our results provide evidence that STAT6 and TATA box regulatory elements play an important role in HgCl2‐induced IL‐4 transcription in rat mast cells.

Mercury induces inflammatory mediator release from human mast cells

“…In contrast, HgCl 2 does not have an effect on its own on release of histamine and IL-4 from human basophil, but only enhances allergic release at concentrations of 1 and 10 μM [12]. This is also true for IL-4 release from rat mast cells [21]. Clinical symptoms of mercury poisoning may be expected at blood levels of 1 μM [12].…”

The Role of T-Helper Cells in Atherosclerosis

“…IL-4 is secreted by several cell types including activated CD4 + T lymphocytes, mast cells, and a specialized subset of CD4 + /NK1.1 + , CD4 + T lymphocytes and mast cells have recently been implicated in inflammatory disorders including autoimmune arthritis and atherosclerosis [152][153][154].…”