title: Overexpression of redox-active protein thioredoxin-1 prevents development of chronic pancreatitis in mice.
abstract: Chronic pancreatitis (CP) is considered to result from repetitive pancreatic injury, and sustained production of various proinflammatory cytokines and chemokines are closely involved in its pathogenesis. Monocyte chemoattractant protein 1 (MCP-1), a member of the CC chemokine family, is believed to contribute to the progression of CP through monocyte/macrophage recruitment. This study aimed to clarify the protective role of thioredoxin-1 (TRX-1), a redox-regulating protein with antioxidative activity, in MCP-1 production and pancreatic fibrosis using a CP model in transgenic mice overexpressing TRX-1 (TRX-1-TG mice) and wildtype C57BL/6 mice. Experimental CP was induced by repeated administration of cerulein and lipopolysaccharide for 6 weeks. In TRX-1-TG mice, pancreatic atrophy was ameliorated, and histologically detectable inflammatory cell infiltration, glandular atrophy, and pseudotubular complex formation were suppressed. Overexpression of TRX-1 also attenuated pancreatic fibrosis and suppressed the activation of pancreatic stellate cells. Serum levels of MCP-1 and pancreatic expression of transforming growth factor-beta, platelet-derived growth factor, and MCP-1 were reduced in TRX-1-TG mice compared with levels in wild-type mice. Overexpression of TRX-1 also reduced H(2)O(2)-induced MCP-1 production in isolated pancreatic acinar cells. These results indicate that TRX-1 can potentially attenuate pancreatic fibrosis via the suppression of oxidative stress and MCP-1-mediated chronic inflammation.
authors.affiliation: Department of Gastroenterology and Hepatology, Tazuke-Kofukai Medical Research Institute and Kitano Hospital, Osaka, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ohashi
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishio
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakamura
authors.forename: Masanori
authors.initials: M
authors.lastname: Asada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tamaki
authors.forename: Kimio
authors.initials: K
authors.lastname: Kawasaki
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fukui
authors.forename: Junji
authors.initials: J
authors.lastname: Yodoi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001284:Atrophy; D002478:Cells, Cultured; D002108:Ceruletide / Q000633:toxicity; D018932:Chemokine CCL2 / Q000097:blood / Q000235:genetics; D004195:Disease Models, Animal; D005355:Fibrosis; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006909:Hydroxyproline / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008315:Malondialdehyde / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D046790:Pancreas, Exocrine / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D011506:Proteins / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D000199:Actins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008070:Lipopolysaccharides; D010982:Platelet-Derived Growth Factor; D011506:Proteins; C491203:TXN protein, human; D016212:Transforming Growth Factor beta; D008315:Malondialdehyde; D013879:Thioredoxins; D002108:Ceruletide; D006861:Hydrogen Peroxide; D006909:Hydroxyproline