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

Abstract

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-kappaB (NF-kappaB) p65, tumor necrosis factor-alpha, interleukin (IL)-1beta, 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-kappaB degradation were analyzed by Western blot.

RESULTS:

Pretreatment of human epithelial HT-29 cells with gliotoxin significantly blocked the I-kappaB degradation and NF-kappaB p65 nuclear translocation induced by tumor necrosis factor-alpha or IL-1beta; 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-kappaB 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-kappaB-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.

• Authors: Chang-Duk Jun, Yurim Kim, Eun-Yong Choi, Minsun Kim, Byungrim Park, Byungsoo Youn, Kangyeol Yu, Kyu-Sil Choi, Kwon-Ha Yoon, Suck-Chei Choi, Myeung-Su Lee, Kie-In Park, Minkyu Choi, Yeuntai Chung, Jaemin Oh
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 12 Issue 7 Pg. 619-29 (Jul 2006) ISSN: 1078-0998 [Print] England
• PMID: 16804400 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Immunosuppressive Agents
• Interleukin-8
• NF-kappa B
• Tumor Necrosis Factor-alpha
• Intercellular Adhesion Molecule-1
• Gliotoxin
• Trinitrobenzenesulfonic Acid
• Peroxidase
• Heme Oxygenase-1

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Body Weight
• Caco-2 Cells
• Colitis (chemically induced, drug therapy)
• Gliotoxin (pharmacology)
• Heme Oxygenase-1 (biosynthesis)
• Humans
• Immunosuppressive Agents (pharmacology)
• Inflammation
• Intercellular Adhesion Molecule-1 (metabolism)
• Interleukin-8 (metabolism)
• Mice
• NF-kappa B (metabolism)
• Peroxidase (metabolism)
• Trinitrobenzenesulfonic Acid (toxicity)
• Tumor Necrosis Factor-alpha (metabolism)