IL-33 Induces Nuocytes and Modulates Liver Injury in Viral Hepatitis

Liang, Yuejin; Jie, Zuliang; Hou, Lifei; Aguilar-Valenzuela, Renan; Vu, David M.; Soong, Lynn; Sun, Jiaren

doi:10.4049/jimmunol.1300117

Cited by 67 publications

(80 citation statements)

References 58 publications

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“…1). Our findings differ from the indirect protection of the liver described for IL-33 following ischemia/reperfusion injury or viral insult, which has been linked to a differential effect on regulatory T lymphocytes, dendritic cells, and macrophages (9,10) or to profibrogenic properties in the liver (11). These differences notwithstanding, the studies point to IL-33 as a soluble factor with both protective and reparative properties in the liver and biliary system.…”

Section: Discussioncontrasting

confidence: 99%

See 1 more Smart Citation

Biliary repair and carcinogenesis are mediated by IL-33–dependent cholangiocyte proliferation

Razumilava

Gores³

et al. 2014

J. Clin. Invest.

179

203

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Injury to the biliary epithelium triggers inflammation and fibrosis, which can result in severe liver diseases and may progress to malignancy. Development of a type 1 immune response has been linked to biliary injury pathogenesis; however, a subset of patients with biliary atresia, the most common childhood cholangiopathy, exhibit increased levels of Th2-promoting cytokines. The relationship among different inflammatory drivers, epithelial repair, and carcinogenesis remains unclear. Here, we determined that the Th2-activating cytokine IL-33 is elevated in biliary atresia patient serum and in the livers and bile ducts of mice with experimental biliary atresia. Administration of IL-33 to WT mice markedly increased cholangiocyte proliferation and promoted sustained cell growth, resulting in dramatic and rapid enlargement of extrahepatic bile ducts. The IL-33-dependent proliferative response was mediated by an increase in the number of type 2 innate lymphoid cells (ILC2s), which released high levels of IL-13 that in turn promoted cholangiocyte hyperplasia. Induction of the IL-33/ILC2/IL-13 circuit in a murine biliary injury model promoted epithelial repair; however, induction of this circuit in mice with constitutive activation of AKT and YAP in bile ducts induced cholangiocarcinoma with liver metastases. These findings reveal that IL-33 mediates epithelial proliferation and suggest that activation of IL-33/ILC2/IL-13 may improve biliary repair and disruption of the circuit may block progression of carcinogenesis.

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Section: Discussioncontrasting

confidence: 99%

“…In the liver, IL-33 appears to be hepatoprotective against Con A and ischemia-reperfusion injury and modulates Treg function in response to HCV infection and chronic fibrosing injuries (8)(9)(10)(11). Here, we report an increase in IL-33 in human and murine biliary atresia.…”

Section: Introductionmentioning

confidence: 63%

Biliary repair and carcinogenesis are mediated by IL-33–dependent cholangiocyte proliferation

Razumilava

Gores³

et al. 2014

J. Clin. Invest.

179

203

View full text Add to dashboard Cite

show abstract

“…3) (Tait Wojno and Artis 2012). Further, ILC2s have also been identified in multiple other tissues including the brain, heart, kidney, muscle, liver, and adipose tissue (Hams et al 2013;Liang et al 2013;McHedlidze et al 2013;Molofsky et al 2013;Nussbaum et al 2013). However, there are a number of questions that remain regarding the function of ILC2s.…”

Section: Discussionmentioning

confidence: 99%

Group 2 Innate Lymphoid Cells in Health and Disease

Kim

Artis

2015

Cold Spring Harb Perspect Biol

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Group 2 innate lymphoid cells (ILC2s) play critical roles in anti-helminth immunity, airway epithelial repair, and metabolic homeostasis. Recently, these cells have also emerged as key players in the development of allergic inflammation at multiple barrier surfaces. ILC2s arise from common lymphoid progenitors in the bone marrow, are dependent on the transcription factors RORa, GATA3, and TCF-1, and produce the type 2 cytokines interleukin (IL)-4, IL-5, IL-9, and/or IL-13. The epithelial cell -derived cytokines IL-25, IL-33, and TSLP regulate the activation and effector functions of ILC2s, and recent studies suggest that their responsiveness to these cytokines and other factors may depend on their tissue environment. In this review, we focus on recent advances in our understanding of the various factors that regulate ILC2 function in the context of immunity, inflammation, and tissue repair across multiple organ systems.

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“…26 Quantitative RT-PCR assays were performed with iQ SYBR Green Supermix and a CFX96 Touch Real-Time PCR Detection System (Bio-Rad, Hercules, CA, USA). The sequences of the forward and reverse gene-specific primers used were the following: GAPDH: forward 59-TGGAAAGCTGTGGCGTGAT-39, reverse 59-TGCTTCACCACCTTCTTGAT-39; IL-7: forward 59-TTCCTCCACTGATCCTTGTTCT-39, reverse 59-AGCAGC-TTCCTTTGTATCATCAC-39; IL-15: forward 59-CATCCATC-TCGTGCTACTTGTG-39, reverse 59-GCCTCTGTTTTAGGG-AGACCT-39.…”

Section: Flow Cytometrymentioning

confidence: 99%

Type 1 interferon-induced IL-7 maintains CD8+ T-cell responses and homeostasis by suppressing PD-1 expression in viral hepatitis

et al. 2014

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Type 1 interferon (IFN-I) promotes antigen-presenting cell maturation and was recently shown to induce hepatic IL-7 production during infection. Herein, we further explored the underlying mechanisms used by IFN-I to orchestrate antiviral immune responses in the liver. Acute viral hepatitis was induced by i.v. injection of adenovirus (Ad) in IFN-a receptor knockout (IFNAR 2/2 ) and control mice. To disrupt signaling, monoclonal antibodies (mAbs) against IL-7 receptor alpha (IL-7Ra) or PD-L1 were i.p. injected. We found that CD8 1 T cells in IFNAR 2/2 mice were less effective than those in control mice. The reduced T-cell function was accompanied by increased levels of PD-1 expression, apoptosis and decreased IFN-c production. The lack of IFN-I signaling also impaired the expression of accessory molecules in both intrahepatic dendritic cell (DCs) and hepatocytes. PD-L1 was comparably and highly expressed on hepatocytes in both IFNAR 2/2 and control mice. Injection of PD-L1-specific mAb in IFNAR 2/2 mice reversed the compromised immune responses in the liver. Further investigation showed that hepatic IL-7 elevation was less pronounced in IFNAR 2/2 mice compared to the controls. A treatment with recombinant IL-7 suppressed PD-1 expression on CD8 1 T cells in vitro. Accordingly, blocking IL-7R signaling in vivo resulted in increased PD-1 expression on CD8 1 T cells in Ad-infected mice. Collectively, the results suggest that IFN-I-induced hepatic IL-7 production maintains antiviral CD8 1 T-cell responses and homeostasis by suppressing PD-1 expression in acute viral hepatitis.

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IL-33 Induces Nuocytes and Modulates Liver Injury in Viral Hepatitis

Cited by 67 publications

References 58 publications

Biliary repair and carcinogenesis are mediated by IL-33–dependent cholangiocyte proliferation

Biliary repair and carcinogenesis are mediated by IL-33–dependent cholangiocyte proliferation

Group 2 Innate Lymphoid Cells in Health and Disease

Type 1 interferon-induced IL-7 maintains CD8+ T-cell responses and homeostasis by suppressing PD-1 expression in viral hepatitis

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