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: Shinya Ohashi, Akiyoshi Nishio, Hajime Nakamura, Masanori Asada, Hiroyuki Tamaki, Kimio Kawasaki, Toshiro Fukui, Junji Yodoi, Tsutomu Chiba
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) 2006 Sep-Oct Vol. 8 Issue 9-10 Pg. 1835-45 ISSN: 1523-0864 [Print] United States
• PMID: 16987036 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Ccl2 protein, mouse
• Chemokine CCL2
• Lipopolysaccharides
• Platelet-Derived Growth Factor
• Proteins
• TXN protein, human
• Transforming Growth Factor beta
• Malondialdehyde
• Thioredoxins
• Ceruletide
• Hydrogen Peroxide
• Hydroxyproline

Topics

• Actins (metabolism)
• Animals
• Atrophy
• Cells, Cultured
• Ceruletide (toxicity)
• Chemokine CCL2 (blood, genetics)
• Disease Models, Animal
• Fibrosis
• Gene Expression (genetics)
• Humans
• Hydrogen Peroxide (pharmacology)
• Hydroxyproline (metabolism)
• Lipopolysaccharides (toxicity)
• Male
• Malondialdehyde (analysis, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Organ Size
• Pancreas (drug effects, metabolism, pathology)
• Pancreas, Exocrine (cytology, drug effects, metabolism)
• Pancreatitis, Chronic (chemically induced, pathology, prevention & control)
• Platelet-Derived Growth Factor (genetics)
• Proteins (metabolism)
• Thioredoxins (genetics, metabolism)
• Transforming Growth Factor beta (genetics)