Yeun-Tai Chung

Gliotoxin reduces the severity of trinitrobenzene sulfonic acid-induced colitis in mice: Evidence of the connection between heme oxygenase-1 and the nuclear factor-κB pathway in vitro and in vivo

Background: Gliotoxin, a fungal metabolite, has been known to show strong immunosuppressive properties, although its mechanisms are not completely understood. In this report, the authors investigated the mechanism whereby gliotoxin has anti‐inflammatory properties in vitro and in trinitrobenzene sulfonic acid‐induced colitis. Materials and Methods: Body weight, histological scores, and myeloperoxidase activity were evaluated in trinitrobenzene sulfonic acid colitis. Nuclear factor‐&kgr;B (NF‐&kgr;B) p65, tumor necrosis factor‐&agr;, interleukin (IL)‐1&bgr;, IL‐12, and intercellular adhesion molecule‐1 were detected by immunohistochemical staining. IL‐8 secretion was measured by an enzyme‐linked immunosorbent assay. Heme oxygenase‐1 (HO‐1) expression and I‐&kgr;B degradation were analyzed by Western blot. Results: Pretreatment of human epithelial HT‐29 cells with gliotoxin significantly blocked the I‐&kgr;B degradation and NF‐&kgr;B p65 nuclear translocation induced by tumor necrosis factor‐&agr; or IL‐1&bgr;; these were parallel with the inhibition of IL‐8 secretion and intercellular adhesion molecule‐1 expression in the same cells. Interestingly, gliotoxin induced HO‐1 in HT‐29 cells and, in turn, inhibition of HO‐1 activity by a zinc protoporphyrin IX reversed the effects of gliotoxin in terms of I‐&kgr;B degradation, intercellular adhesion molecule‐1 expression, and IL‐8 production. In trinitrobenzene sulfonic acid colitis, gliotoxin administration significantly improved the clinical and histopathological symptoms. Notably, gliotoxin also induced HO‐1 in the colonic mucosa and zinc protoporphyrin IX reversed the protective effects of gliotoxin in trinitrobenzene sulfonic acid colitis. Conclusions: These results demonstrate for the first time that the anti‐inflammatory actions mediated by gliotoxin include HO‐1 induction and the subsequent blockade of NF‐&kgr;B‐dependent signaling pathways in vitro and in vivo. The current results also demonstrate that gliotoxin may be an effective agent for the treatment of diseases characterized by mucosal inflammation.