Depletion of Foxp3+ Regulatory T Cells Promotes Profibrogenic Milieu of Cholestasis-Induced Liver Injury

Overview

Journal Dig Dis Sci

Specialty Gastroenterology

Date 2014 Nov 23

PMID 25416630

Citations 18

Authors

Yoon Seok Roh

Surim Park

Chae Woong Lim

Bumseok Kim

Affiliations

Soon will be listed here.

Abstract

Background: Accumulating evidence suggests that Foxp3+ regulatory T (Treg) cells act as inhibitory mediators of inflammation; however, the in vivo mechanism underlying this protection remains elusive in liver diseases.

Aims: To clarify the in vivo role of Foxp3+ Treg cells in liver fibrosis, we used the DEREG mouse, which expresses the diphtheria toxin receptor under control of the Foxp3 promoter, allowing for specific deletion of Foxp3+ Treg cells.

Methods: Bile duct ligation-induced liver injury and fibrosis were assessed by histopathology, fibrogenic gene expression, and measurement of cytokine and chemokine levels.

Results: Depletion of Foxp3+ Treg cells enhanced Th17 cell response as demonstrated by the increase of IL-17+ cells and related gene expressions including Il17f, Il17ra, and Rorgt in the fibrotic livers of DEREG mice. Of note, infiltration of CD8+ T cells and Cd8 gene expression was significantly increased in the livers of DEREG mice. Consistent with increased IL-17+ and CD8+ T cell responses, DEREG mice generated higher levels of inflammatory cytokines (TNF-α, IL-6, and IL-12p70) and chemokines (MCP-1, MIP-1α, and RANTES). These results were concordant with severity of liver fibrosis and hepatic enzyme levels (ALT and ALP).

Conclusions: The present findings demonstrate that Foxp3+ Treg cells inhibit the profibrogenic inflammatory milieu through suppression of pro-fibrogenic CD8+ and IL-17+ T cells.

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