Inhibition of Cytokine Production and Interference in IL-2 Receptor-mediated Jak-Stat Signaling by the Hydroxylamine Metabolite of Sulfamethoxazole
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Sulfonamides, used for the treatment of opportunistic infections in immunocompromised patients, are associated with a high incidence of adverse drug events, including severe hypersensitivity reactions. Imbalances in the production and detoxification of reactive sulfonamide metabolites have been implicated in the pathogenesis of these life-threatening reactions. The hydroxylamine metabolite of sulfamethoxazole (SMX-HA) inhibits the proliferation of mitogen-stimulated peripheral blood mononuclear cells (PBMCs) in vitro without reducing Interleukin 2 (IL-2) expression. We investigated the effects of SMX-HA on accessory cytokine expression and IL-2 receptor (IL-2R) mediated signal transduction. SMX-HA did not reduce significantly mRNA production of proinflammatory [tumor necrosis factor a (TNF-a) and IL-1b], Th1-type (IFN-g), and Th2-type cytokines (IL-4 and IL-10). Sublethal concentrations of SMX-HA (25 mM) reduced significantly the production of TNF-a, IL-1b, and IL4 protein without inhibiting the production of IFN-g. This finding suggests that exposure to SMX-HA might direct a response towards a Th-1 vs. a Th-2 response. Immunoblot analysis of IL-2R-mediated Janus kinases and signal transduction activators of transcription (Jak-Stat) signal transduction revealed diminished phosphorylation of Jak1 and Jak3 and inhibited downstream phosphorylation of Stat3, Stat5a, and IL-2Rg in phytohemagglutinin/rIL-2 activated PBMCs treated with SMX-HA. SMX-HA did not inhibit Jak association with IL-2Rg or IL-2Rb. These data illustrated that sublethal concentrations of SMX-HA interfere with IL-2R-mediated signal transduction, resulting in altered cytokine production and inhibition of lymphocyte proliferation.