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(American Journal of Pathology. 2004;165:1907-1920.)
© 2004 American Society for Investigative Pathology

Regulation and Function of Trefoil Factor Family 3 Expression in the Biliary Tree

Isao Nozaki*{dagger}, John G. Lunz, III*{dagger}{ddagger}, Susan Specht*{ddagger}, Jong-In Park§, Andrew S. Giraud, Noriko Murase*{ddagger} and Anthony J. Demetris*{dagger}

From the Thomas E. Starzl Transplantation Institute* and the Departments of Pathology{dagger} and Surgery,{ddagger} Divisions of Transplantation, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; the Sidney Kimmel Comprehensive Cancer Center at John Hopkins,§ The John Hopkins University School of Medicine, Baltimore, Maryland; and the Department of Medicine, University of Melbourne Western Hospital, Footscray, Victoria, Australia

Microarray analysis identified trefoil factor family 3 (TFF3) as a gene expressed in biliary epithelial cells (BECs), regulated by interleukin (IL)-6, and potentially involved in biliary pathophysiology. We therefore studied the regulation and function of BEC TFF3, in vitro and in vivo in IL-6+/+ and IL-6–/– mice subjected to chronic bile duct ligation for 12 weeks. In vitro studies showed that IL-6 wild-type (IL-6+/+) BECs expressed higher TFF3 mRNA and protein levels than IL-6-deficient (IL-6–/–) BECs. BEC TFF3 expression is dependent primarily on signal transducer and activator of transcription (STAT3) signaling, but the reciprocal negative regulation known to exist between the intracellular IL-6/gp130 signaling pathways, STAT3 and mitogen-activated protein kinase (MAPK), importantly contributes to BEC TFF3 expression. Specifically blocking STAT3 activity with a dominant-negative molecule or treatment with a growth factor such as hepatocyte growth factor, which increases MAPK signaling, decreases BEC TFF3 expression. In contrast, specifically blocking MAPK activity with PD98059 significantly increased BEC TFF3 expression. Higher BEC TFF3 levels in IL-6+/+ BECs were associated with significantly better migration than IL-6–/– BECs in a wound-healing assay and defective IL-6–/– BEC migration was reversed with exogenous TFF3. In vivo, hepatic TFF3 mRNA and protein expression was limited to BECs and dependent significantly on STAT3 signaling, but was influenced by other factors present after bile duct ligation. Comparable results were obtained in normal and diseased human tissue samples. In conclusion the regulation and function of BEC TFF3 expression is similar to the colon. BEC TFF3 expression depends primarily on gp130/STAT3 and contributes to BEC migration and wound healing. Therefore, use of recombinant IL-6 or TFF3 peptides should exert a therapeutic role in preventing biliary strictures in liver allografts.




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