Journal of Surgical Research
Volume 141, Issue 2 , Pages 183-191, August 2007

Paclitaxel Interrupts TGF-β1 Signaling Between Gallbladder Epithelial Cells and Myofibroblasts

  • Ho-Soon Choi, M.D.

      Affiliations

    • H.-S.C.’s current address is Division of Gastroenterology, Hanyang University Hospital, Seoul, Korea. J.-W.C.’s current address is Department of General Surgery, College of Medicine, Chungbuk National University, Cheongju, Korea.
    • ,
  • Christopher E. Savard, M.S.
    • ,
  • Jae-Woon Choi, M.D.
    • ,
  • Rahul Kuver, M.D.

      Affiliations

    • Corresponding Author InformationTo whom correspondence and reprint requests should be addressed at Box 356424, Division of Gastroenterology, University of Washington, 1959 NE Pacific St., Seattle, WA 98195.
    • ,
  • Sum P. Lee, M.D., Ph.D.

Division of Gastroenterology, Department of Medicine, University of Washington, and Puget Sound Veterans Affairs Health Care System, Seattle, Washington

Received 17 May 2006 published online 16 June 2007.

Background

The cellular and molecular mechanisms of fibrogenesis in the extrahepatic biliary epithelium are not known. Transforming growth factor-β1 (TGF-β1) is a cytokine implicated in signaling pathways that mediate collagen formation. An observation that paclitaxel (PT), applied topically into the rat common bile duct, inhibited stricture formation led us to hypothesize that PT’s effects might be due to interruption of TGF-β1 signaling between biliary epithelial cells and subepithelial myofibroblasts.

Materials and methods

We tested this hypothesis using an in vitro cell-culture model in which murine gallbladder epithelial cells (GBEC) are cultured separately or cocultured with human gallbladder myofibroblasts (GBMF).

Results

Exposure to Escherichia coli lipopolysaccharide (LPS) enhanced TGF-β1 mRNA expression and stimulated TGF-β1 protein secretion into both apical and basolateral compartments in GBEC. This effect was more prominent with basolateral secretion and was also more pronounced in the coculture system. In GBMF, collagen I mRNA expression and protein secretion were stimulated by treatment with LPS or TGF-β1. GBMF also expressed TGF-β1 mRNA, whose levels were enhanced by exposure to either LPS or exogenous TGF-β1. PT inhibited LPS-induced TGF-β1 mRNA expression and protein secretion in GBEC in both culture systems. Tumor necrosis factor-α mRNA expression and protein secretion were not affected by PT in GBEC, demonstrating that the effects were specific for TGF-β1. PT also inhibited LPS- and TGF-β1-induced collagen I mRNA expression and protein secretion in GBMF.

Conclusions

These findings support a model in which GBEC communicate with subepithelial GBMF via TGF-β1, leading to collagen deposition and fibrosis, and in which GBMF possess autocrine mechanisms involving TGF-β1 that could regulate collagen production. PT inhibits these fibrogenic pathways.

Key Words: biliary epithelium, cholangitis, fibrosis, gallstones

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PII: S0022-4804(06)01183-8

doi:10.1016/j.jss.2006.12.558

Journal of Surgical Research
Volume 141, Issue 2 , Pages 183-191, August 2007

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