Faculty Collaboration Database

Regulation and function of trefoil factor family 3 expression in the biliary tree. Am J Pathol 2004 Dec;165(6):1907-20

Date

12/08/2004

Pubmed ID

15579435

Pubmed Central ID

PMC1618723

DOI

10.1016/S0002-9440(10)63243-9

Scopus ID

2-s2.0-9644257445 (requires institutional sign-in at Scopus site)   45 Citations

Abstract

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.

Author List

Nozaki I, Lunz JG 3rd, Specht S, Park JI, Giraud AS, Murase N, Demetris AJ

Author

Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Bile Ducts
Cell Movement
DNA-Binding Proteins
Enzyme Inhibitors
Epithelial Cells
Gene Expression Regulation
Genes, Dominant
Hepatocyte Growth Factor
Interleukin-6
Male
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinases
Mucins
Oligonucleotide Array Sequence Analysis
STAT3 Transcription Factor
Signal Transduction
Trans-Activators
Trefoil Factor-3
Wound Healing