Therapeutic agents that block the
nuclear factor-kappa B (NF-κB) pathway might be beneficial for incurable inflammatory diseases, such as
ulcerative colitis. Here, we investigated the effect of the novel NF-κB inhibitor
celastrol on murine
colitis.
Colitis was induced in male mice by administration of 5% (w/v)
dextran sulfate sodium (DSS) in
drinking water for a period of 5 days, followed by a 2 day recovery period.
Celastrol (2mg/kg, oral) was administered daily over the 1 week of the study. Our results indicated that treatment with
celastrol attenuated DSS-induced colon shortening and neutrophil infiltration. Besides,
celastrol ameliorated DSS-induced colon injury and inflammatory signs as visualized by histopathology. The mechanisms behind these beneficial effects of
celastrol were also elucidated. These include (i) counteracting DSS-induced oxidative stress in the colon via decreasing lipid peroxidation products (
malondialdehyde and 4-hydroxynonenal) and increasing the
antioxidant levels (
reduced glutathione,
glutathione-S-transferase and
superoxide dismutase); (ii) inhibiting DSS-induced activation of the NLRP3-inflammasome, as evidenced by decreased production of IL-1β and IFN-γ as indirect measure of
IL-18 in the colon; (iii) targeting DSS-induced activation of the IL-23/IL-17 pathway by abating the elevation of
IL-23 and
IL-17A levels in the colon; (iv) augmenting the anti-inflammatory defense mechanisms via increasing
IL-10 and TNF-α levels in the colon; (v) and more importantly, maintaining intestinal epithelial reconstitution and homeostasis via attenuating the overexpression of CD98 in colonic epithelial cells. In conclusion, our study provides novel insights into the beneficial effects of
celastrol as a promising candidate for the treatment of
ulcerative colitis in humans.