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.
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.


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.
Jun
Chang-Duk
CD
Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
Kim
Yurim
Y
Choi
Eun-Yong
EY
Kim
Minsun
M
Park
Byungrim
B
Youn
Byungsoo
B
Yu
Kangyeol
K
Choi
Kyu-Sil
KS
Yoon
Kwon-Ha
KH
Choi
Suck-Chei
SC
Lee
Myeung-Su
MS
Park
Kie-In
KI
Choi
Minkyu
M
Chung
Yeuntai
Y
Oh
Jaemin
J
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001835:Body Weight; D018938:Caco-2 Cells; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy; D005912:Gliotoxin / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D016209:Interleukin-8; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D005912:Gliotoxin; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase; D051547:Heme Oxygenase-1