Alimentary TractSuppression of NF-κB activity by sulfasalazine is mediated by direct inhibition of IκB kinases α and β☆,☆☆
Section snippets
Cell culture and treatments
Jurkat T cells were grown in RPMI, and SW620 colonic epithelial cells were grown in Dulbecco's modified Eagle medium supplemented with 10% fetal calf serum, 2 mmol/L glutamine, and 1% (wt/vol) penicillin/streptomycin. Recombinant human TNF-α, TPA, sulfasalazine, 4-aminosalicylic acid (4-ASA), 5-aminosalicylic acid (5-ASA), sulfapyridine, and acetylsalicylic acid (aspirin, ASA) were purchased from Sigma (Deisenhofen, Germany). Sulfasalazine, 4-ASA, 5-ASA, sulfapyridine, and aspirin were
Inhibition of NF-κB/Rel activation and κB-dependent transcription in jurkat T cells
NF-κB/Rel activity of Jurkat T cells induced by TNF-α was analyzed by electrophoretic mobility shift assay in the presence or absence of sulfasalazine (Figure 1A).
Discussion
Most of the beneficial effects of salicylates such as sulfasalazine are attributed to their inhibition of cyclooxygenase and prostaglandin H synthase; however, prostaglandin-independent effects, such as inhibition of the transcription factor NF-κB/Rel, have been shown.10 We previously demonstrated that sulfasalazine inhibits NF-κB/Rel activation induced by TNF-α, lipopolysaccharide, and TPA in a colonic epithelial cell line.13 The molecular mechanism for this inhibition remained unclear. In
Acknowledgements
The authors thank Esther Rüber and Sabine Schirmer for excellent technical assistance; Sonja Aigner for help in preparing the manuscript; Michael Karin (San Diego, California) for plasmids GST-IκBα (1-54) and GST-IκBα (1-54,S32A,S36A) and expression vectors for HA-IKK-α, HA-IKK-α, HA-IKK-EEα, HA-IKK-EEβ, and NIK; J. Li (Department of Biology, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT) for recombinant IKK-α and IKK-β purified from Sf9 cells; and Joseph Slupsky for critical reading of
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Address requests for reprints to: Roland M. Schmid, M.D., Department of Internal Medicine I, University of Ulm, Robert-Koch-Strasse 8, D-89081 Ulm, Germany. e-mail: [email protected]; fax: (49) 731-50-24302.
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Supported in part by grants from the Novartis-Stiftung für Therapeutische Forschung and Deutsche Krebshilfe (to R.M.S. and S.L.).