title: 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.
  
  
  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.affiliation: Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
authors.forename: Chang-Duk
authors.initials: CD
authors.lastname: Jun
authors.forename: Yurim
authors.initials: Y
authors.lastname: Kim
authors.forename: Eun-Yong
authors.initials: EY
authors.lastname: Choi
authors.forename: Minsun
authors.initials: M
authors.lastname: Kim
authors.forename: Byungrim
authors.initials: B
authors.lastname: Park
authors.forename: Byungsoo
authors.initials: B
authors.lastname: Youn
authors.forename: Kangyeol
authors.initials: K
authors.lastname: Yu
authors.forename: Kyu-Sil
authors.initials: KS
authors.lastname: Choi
authors.forename: Kwon-Ha
authors.initials: KH
authors.lastname: Yoon
authors.forename: Suck-Chei
authors.initials: SC
authors.lastname: Choi
authors.forename: Myeung-Su
authors.initials: MS
authors.lastname: Lee
authors.forename: Kie-In
authors.initials: KI
authors.lastname: Park
authors.forename: Minkyu
authors.initials: M
authors.lastname: Choi
authors.forename: Yeuntai
authors.initials: Y
authors.lastname: Chung
authors.forename: Jaemin
authors.initials: J
authors.lastname: Oh
mesh_terms: 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
chemical_list: 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