SULFASALAZINE - A POTENT AND SPECIFIC INHIBITOR OF NUCLEAR FACTOR KAPPA-B

Transcription factors of the NF-kappa B/Rel family are critical for in ducible expression of multiple genes involved in inflammatory response s, Sulfasalazine and its salicylate moiety 5-aminosalicylic acid are a mong the most effective agents for treating inflammatory bowel disease and rheumatoid arthritis. However, the mode of action of these drugs remains unclear. Here we provide evidence that the transcription facto r NF-kappa B is a target of sulfasalazine-mediated immunosuppression. Treatment of SW620 colon cells with sulfasalazine inhibited TNF alpha- , LPS-, or phorbol ester-induced NF-kappa B activation. NF-kappa B-dep endent transcription was inhibited by sulfasalazine at micro- to milli molar concentrations. In contrast, 5-aminosalicylic acid or sulfapyrid ine did not block NF-kappa B activation at all doses tested, TNF alpha -induced nuclear translocation of NF-kappa B was prevented by sulfasal azine through inhibition of I kappa B alpha degradation. When blocking proteasome-mediated degradation of I kappa B alpha, we could demonstr ate that sulfasalazine interfered with I kappa B alpha phosphorylation , suggesting a direct effect on an I kappa B alpha kinase or on an ups tream signal. Inhibition of NF-kappa B activation seems to be specific since other DNA-binding activities such as AP1 were not affected. The se results demonstrate that sulfasalazine is a potent and specific inh ibitor of NF-kappa B activation, and thus may explain some of the know n biological properties of sulfasalazine.