Physiology and Pharmacology Publications


Inhibition of Cytokine Production and Interference in IL-2 Receptor-mediated Jak-Stat Signaling by the Hydroxylamine Metabolite of Sulfamethoxazole

Document Type


Publication Date



FASEB Journal





First Page


Last Page


URL with Digital Object Identifier



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.

Find in your library