Regulation and function of trefoil factor family 3 expression in the biliary tree.
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.
Nozaki
Isao
I
Thomas E. Starzl Transplantation Institute, Division of Transplantation, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
Lunz
John G
JG
Specht
Susan
S
Park
Jong-In
JI
Giraud
Andrew S
AS
Murase
Noriko
N
Demetris
Anthony J
AJ
D000818:Animals; D001652:Bile Ducts / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009077:Mucins / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D000071165:Trefoil Factor-3; D014945:Wound Healing
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D009077:Mucins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C493263:Tff3 protein, mouse; D015534:Trans-Activators; D000071165:Trefoil Factor-3; D017228:Hepatocyte Growth Factor; D020928:Mitogen-Activated Protein Kinases