Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B.

Abstract

Transcription factors of the NF-kappaB/Rel family are critical for inducible expression of multiple genes involved in inflammatory responses. Sulfasalazine and its salicylate moiety 5-aminosalicylic acid are among 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 factor NF-kappaB is a target of sulfasalazine-mediated immunosuppression. Treatment of SW620 colon cells with sulfasalazine inhibited TNFalpha-, LPS-, or phorbol ester- induced NF-kappaB activation. NF-kappaB-dependent transcription was inhibited by sulfasalazine at micro- to millimolar concentrations. In contrast, 5-aminosalicylic acid or sulfapyridine did not block NF-kappaB activation at all doses tested. TNFalpha-induced nuclear translocation of NF-kappaB was prevented by sulfasalazine through inhibition of IkappaBalpha degradation. When blocking proteasome-mediated degradation of IkappaBalpha, we could demonstrate that sulfasalazine interfered with IkappaBalpha phosphorylation, suggesting a direct effect on an IkappaBalpha kinase or on an upstream signal. Inhibition of NF-kappaB activation seems to be specific since other DNA-binding activities such as AP1 were not affected. These results demonstrate that sulfasalazine is a potent and specific inhibitor of NF-kappaB activation, and thus may explain some of the known biological properties of sulfasalazine.

Role of NF-κB in Cytokine Production Induced from Human Airway Epithelial Cells by Rhinovirus Infection

“…Sulfasalazine has been reported to inhibit NF-B activation by interfering with phosphorylation of I B␣ (31). In HRV-16-infected epithelial cells, sulfasalazine (2 mM) prevented activation of NF-B, as assessed by binding to the oligonucleotides from both the IL-6 and IL-8 gene promoters (Fig.…”

Treatment of Diarrhea-Predominant Irritable Bowel Syndrome With Mesalazine and/or Saccharomyces Boulardii

“…Although the exact mechanism of action of mesalazine has still to be elucidated, several potential mechanisms have been suggested, including 5-aminosalicylate-induced inhibition of inflammation by interfering with the metabolism of arachidonic acid, prevention of mucosal generation of leukotrienes and prostaglandins, scavenging of free radicals and mechanisms only recently identified involving inhibition of nuclear factor-kappaB (NFB) and induction of apoptosis (6,18,31,43,47,48,55,57,59) . Additional relevant properties include changes in the production of immune globulins and diminished production of interleukin-1 and partial inhibition of platelet activating factor (PAF) expression, resulting in a decrease in leucocyte trafficking (32) .…”

Treatment of postinfectious irritable bowel syndrome and noninfective irritable bowel syndrome with mesalazine

“…Although its exact mechanism are still unknown (10,20) , several potential mechanisms have been suggested, including 5-aminosalicylate-induced inhibition of inflammation by interfering with the metabolism of arachidonic acid, prevention of mucosal generation of leukotrienes and PG (26) scavenging of free radicals (21,26) and mechanisms only recently identified involving inhibition of nuclear factor-kappaB (NFκB) and induction of apoptosis (4,15,19,27,28) .…”