Fumaric acid esters and inflammatory responses

Background and Aims: Fumaric acid esters have been proven to be effective for the systemic treatment of psoriasis and multiple sclerosis. We aimed to develop a new treatment for colitis. Methods: We investigated the effect of dimethylfumarate (DMF, 10-30-100 mg/kg) on an experimental model of colitis induced by DNBS. We also evaluated the therapeutic activity of 7 weeks treatment of DMF (30 mg/kg) on 9-week-old IL-10KO mice that spontaneously develop a Th1-dependent chronic enterocolitis after birth that is fully established at 8-10 weeks of age. The mechanism of this pharmacological potential of DMF (10μM) was investigated in colonic epithelial cell monolayers (Caco-2) exposed to H2O2. The barrier function was evaluated by the tight junction proteins. Results: The treatment with DMF significantly reduced the degree of hemorrhagic diarrhea and weight loss caused by administration of DNBS. DMF (30 and 100 mg/kg) also caused a substantial reduction in the degree of colon injury, in the rise in MPO activity, in the increase in TNF-α expression, as well as in the up-regulation of ICAM-1 caused by DNBS in the colon. Molecular studies demonstrated that DMF impaired NF-κB signaling via reduced p65 nuclear translocalization. DMF induced a stronger antioxidant response as evidenced by a higher expression of Mn-superoxide dismutase. Moreover, DMF protected human intestinal epithelial cells against H2O2-induced barrier dysfunction, restoring ZO-1, occludin expression, via the HO-1 pathway. Conclusions: DMF treatment reduces the degree of colitis caused by DNBS. We propose that DMF treatment may be useful in the treatment of inflammatory bowel disease.