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

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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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Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning (2014R1A1A1006622) and by the Brain Korea 21 Plus Program in 2013.

Conflict of interest

None.

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Authors and Affiliations

  1. Laboratory of Pathology, College of Veterinary Medicine (BK21 Plus Program), Chonbuk National University, Jeonju, 561-756, South Korea

    Yoon Seok Roh, Surim Park, Chae Woong Lim & Bumseok Kim

  2. Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA

    Yoon Seok Roh

  3. Biosafety Research Institute, Jeonju, South Korea

    Yoon Seok Roh, Surim Park, Chae Woong Lim & Bumseok Kim

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  1. Yoon Seok Roh
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Correspondence to Bumseok Kim.

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Roh, Y.S., Park, S., Lim, C.W. et al. Depletion of Foxp3+ Regulatory T Cells Promotes Profibrogenic Milieu of Cholestasis-Induced Liver Injury. Dig Dis Sci 60, 2009–2018 (2015). https://doi.org/10.1007/s10620-014-3438-2

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  • DOI: https://doi.org/10.1007/s10620-014-3438-2

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