Obstructive Jaundice Expands Intrahepatic Regulatory T Cells, Which Impair Liver T Lymphocyte Function but Modulate Liver Cholestasis and Fibrosis

Katz, Steven C.; Ryan, Kristin; Ahmed, Naseem; Plitas, George; Chaudhry, Umer I.; Kingham, T. Peter; Naheed, Seema; Nguyen, Cang T.; Somasundar, Ponnandai; Espat, N. Joseph; Junghans, Richard P.; DeMatteo, Ronald P.

doi:10.4049/jimmunol.1004077

Cited by 71 publications

(57 citation statements)

References 39 publications

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“…Preliminary studies indicate that the number of Tregs is increased in mice following bile duct ligation and that depletion of Tregs enhances cholestasis, inflammation, and fibrosis (40). Although these data suggest a protective role of Tregs during liver fibrosis, further studies are needed inasmuch as Tregs are also known to release profibrogenic mediators such as TGF-␤ (95).…”

Section: Adaptive Immune Cells T Lymphocytes Cd4mentioning

confidence: 99%

Cellular Mechanisms of Tissue Fibrosis. 5. Novel insights into liver fibrosis

Mallat

Lotersztajn

2013

American Journal of Physiology-Cell Physiology

196

220

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Liver fibrosis is the common scarring reaction associated with chronic liver injury that results from prolonged parenchymal cell injury and/or inflammation. The fibrogenic response is characterized by progressive accumulation of extracellular matrix components enriched in fibrillar collagens and a failure of matrix turnover. This process is driven by a heterogeneous population of hepatic myofibroblasts, which mainly derive from hepatic stellate cells and portal fibroblasts. Regression of fibrosis can be achieved by the successful control of chronic liver injury, owing to termination of the fibrogenic reaction following clearance of hepatic myofibroblasts and restoration of fibrolytic pathways. Understanding of the complex network underlying liver fibrogenesis has allowed the identification of a large number of antifibrotic targets, but no antifibrotic drug has as yet been approved. This review will highlight recent advances regarding the mechanisms that regulate liver fibrogenesis and fibrosis regression, with special focus on novel signaling pathways and the role of inflammatory cells. Translation of these findings to therapies will require continued efforts to develop multitarget therapeutic approaches that will improve the grim prognosis of liver cirrhosis.

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Section: Adaptive Immune Cells T Lymphocytes Cd4mentioning

confidence: 99%

Cellular Mechanisms of Tissue Fibrosis. 5. Novel insights into liver fibrosis

Mallat

Lotersztajn

2013

American Journal of Physiology-Cell Physiology

196

220

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“…1 forkhead box P3 1 Tregs are mediators of immune tolerance, express Toll-like receptors including TLR4, exert enhanced suppressor function in response to LPS treatment, and have previously been shown to contribute to extrahepatic cholestasis (Caramalho et al, 2003;Katz et al, 2011). Additional studies to identify which lymphocytes are involved and gain a better understanding of their mechanism(s) of action during acute and chronic exposure are required to appropriately address this question.…”

Section: Lymphocytes On Hepatic Cytokines and Transportersmentioning

confidence: 99%

Differential Regulation of Hepatic Organic Cation Transporter 1, Organic Anion-Transporting Polypeptide 1a4, Bile-Salt Export Pump, and Multidrug Resistance-Associated Protein 2 Transporter Expression in Lymphocyte-Deficient Mice Associates with Interleukin-6 Production

Bodeman

Dzierlenga

Tally

et al. 2013

The Journal of Pharmacology and Experimental Therapeutics

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Cholestasis results from interrupted bile flow and is associated with immune-mediated liver diseases. It is unclear how inflammation contributes to cholestasis. The aim of this study was to determine whether T and B cells contribute to hepatic transporter expression under basal and inflammatory conditions. C57BL/6J wild-type mice or strains lacking T, B, or both T and B cells were exposed to lipopolysaccharide (LPS) or saline, and livers were collected 16 hours later. Branched DNA signal amplification was used to assess mRNA levels of organic anion-transporting polypeptides (Oatp) 1a1, 1a4, and 1b2; organic cation transporter (Oct) 1; canalicular bile-salt export pump (Bsep); multidrug resistance-associated proteins (Mrp) 2 and 3; and sodium-taurocholate cotransporting polypeptide (Ntcp). Real-time polymerase chain reaction analysis was used to correlate changes of transporter expression with interleukin-1b (IL-1b), IL-6, IL-17A, IL-17F, tumor necrosis factor-a (TNF-a), and interferon-g expression in the liver. LPS treatment inhibited Bsep and Oct1 mRNA expression, and this was abrogated with a loss of T cells, but not B cells. In addition, the absence of T cells increased Mrp2 mRNA expression, whereas B cell deficiency attenuated Oatp1a4 mRNA in LPS-treated mice. Oatp1a1, Oatp1b2, Ntcp, and Mrp3 were largely unaffected by T or B cell deficiency. Lymphocyte deficiency altered basal and inflammatory IL-6, but not TNF-a or IL-1b, mRNA expression. Taken together, these data implicate lymphocytes as regulators of basal and inflammatory hepatic transporter expression and suggest that IL-6 signaling may play a critical role.

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“…Tregs were also involved in the liver repair and fibrosis process. In a bile duct ligation rat model, Treg depletion exacerbated hepatic fibrosis and cholestasis, which was related to significant changes in IL-6 and IL-10 production [18]. In chronic hepatitis C virus infection, Tregs were enriched in areas of fibrosis [19], and IL-8-producing Treg acted on hepatic stellate cells and functioned as a pro-fibrogenic factor [20].…”

Section: Treg-mediated Repair At Multiple Tissuesmentioning

confidence: 99%

‘Repair’ Treg Cells in Tissue Injury

Zhang

Feng

et al. 2017

Cell Physiol Biochem

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Studies in mice and humans have elucidated an important role for Tregs in promoting tissue repair and restoring tissue integrity. Emerging evidence has revealed that Tregs promoted wound healing and repair processes at multiple tissue sites, such as the heart, liver, kidney, muscle, lung, bone and central nervous system. The localization of repair Tregs in the lung, muscle and liver exhibited unique phenotypes and functions. Epidermal growth factor receptor, amphiregulin, CD73/CD39 and keratinocyte growth factor are important repair factors that are produced or expressed by repair Tregs; these factors coordinate with parenchymal cells to limit injury and promote repair. In addition, repair Tregs can be modulated by IL-33/ST2, TCR signals and other cytokines in the context of injured microenvironment cues. In this review, we provide an overview of the emerging knowledge about Treg-mediated repair in damaged tissues and organs.

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Obstructive Jaundice Expands Intrahepatic Regulatory T Cells, Which Impair Liver T Lymphocyte Function but Modulate Liver Cholestasis and Fibrosis

Cited by 71 publications

References 39 publications

Cellular Mechanisms of Tissue Fibrosis. 5. Novel insights into liver fibrosis

Cellular Mechanisms of Tissue Fibrosis. 5. Novel insights into liver fibrosis

Differential Regulation of Hepatic Organic Cation Transporter 1, Organic Anion-Transporting Polypeptide 1a4, Bile-Salt Export Pump, and Multidrug Resistance-Associated Protein 2 Transporter Expression in Lymphocyte-Deficient Mice Associates with Interleukin-6 Production

‘Repair’ Treg Cells in Tissue Injury

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