The critical molecular events that regulate immune control vs. disease pathogenesis in viral hepatitis remain elusive. However, recent reports suggested that patients with chronic hepatitis displayed elevated concentrations of alarmin (IL-33) and its decoy receptor sST2 in the serum. Their levels were associated with hepatic damage, viral and clinical outcomes in response to antiviral therapy. We hypothesize that IL-33 can directly engage innate and adaptive immune systems in the liver and also induce differentiation of novel group 2 innate lymphoid cells (ILC2). Through these actions, IL-33 can modulate immune responses and protect the liver during the inflammatory process. Two complementary approaches are proposed to test these hypotheses. 1) To examine if IL-33 protects the liver in acute hepatitis and persistent viral infection. In this Aim, we will examine he endogenous levels of IL-33 and its receptor ST2 in the liver and serum following i.v. delivery of recombinant adenovirus (rAd). To investigate the IL-33/ST2 pathway in persistent viral infection, we will also examine hepatitis induced by lymphocytic choriomeningitis virus clone 13 (LCVM CL13) and antiviral immune responses in these animals. The function of IL-33 will be assessed in IL-33-/- mice as well as by anti-ST2 mAb in wild-type (wt) animals. Conversely, we will treat infected animals with rIL-33 to evaluate its protective functions. 2) To analyze IL-33-induced immune mechanisms responsible for enhanced immune responses and ameliorated liver injury. Our working hypothesis is that IL-33 can directly act on T effector cells or through inducing ILC2s in the liver. We will test the possibility that IL-33 not only enhances T cell vigor but also expands its antigenic breadth using a reconstituted LCMV TCR transgenic mouse (P14) model. In preliminary studies, we found that IL-33 can enhance IFN-? but inhibit TNF-? production. We hypothesize that pro-IL-33, an unprocessed nucleoprotein, can act as a transcriptional factor to modulate the effector cytokines expression on T cells. To examine the IL-33 and DNA interaction, we will use a two-step ChIP assay to determine whether IL-33 binds and sequesters NF-?B signal for TNF-? expression. We anticipate that lack of IL-33 in the knockout animals will lead NF-?B signaling and TNF-? dysregulation, leading to exacerbated liver injury. The new evidence from this study may explain clinical observations that damage-associated molecules like IL-33 and its receptor correlates to T responses and clinical prognosis in patients with chronic hepatitis and drug-induced hepatotoxicity. Such findings would be potentially paradigm-shifting. Although this research is exploratory in nature, it has strong potential to be developed to more detailed studies involving future therapeutic candidates and human subjects infected with hepatitis virus.

Public Health Relevance

Hepatitis caused by virus is a serious liver disease in most patients. However, divergent immune responses can result in markedly different clinical courses, ranging from mild inflammation to fulminant hepatitis, cancer development and liver failure. The goal of this proposal is to understand how the events taking place in liver tissue can influence antiviral immune responses and disease outcomes, and the experimental results can lead to much needed insights and potential therapeutic candidates for hepatitis treatment and prevention.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Koshy, Rajen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Medical Br Galveston
Schools of Medicine
United States
Zip Code
Liang, Yuejin; Yi, Panpan; Yuan, Denley Ming Kee et al. (2018) IL-33 induces immunosuppressive neutrophils via a type 2 innate lymphoid cell/IL-13/STAT6 axis and protects the liver against injury in LCMV infection-induced viral hepatitis. Cell Mol Immunol :
Jie, Zuliang; Liang, Yuejin; Yi, Panpan et al. (2017) Retinoic Acid Regulates Immune Responses by Promoting IL-22 and Modulating S100 Proteins in Viral Hepatitis. J Immunol 198:3448-3460
Shelite, Thomas R; Liang, Yuejin; Wang, Hui et al. (2016) IL-33-Dependent Endothelial Activation Contributes to Apoptosis and Renal Injury in Orientia tsutsugamushi-Infected Mice. PLoS Negl Trop Dis 10:e0004467
Liang, Yuejin; Kwota, Zakari; Sun, Jiaren (2016) Intrahepatic regulation of antiviral T cell responses at initial stages of viral infection. Int Immunopharmacol 39:106-112
Hou, Lifei; Jie, Zuliang; Liang, Yuejin et al. (2015) Type 1 interferon-induced IL-7 maintains CD8+ T-cell responses and homeostasis by suppressing PD-1 expression in viral hepatitis. Cell Mol Immunol 12:213-21
Hou, Lifei; Wang, Tian; Sun, Jiaren (2015) ?? T cells in infection and autoimmunity. Int Immunopharmacol 28:887-91
Liang, Yuejin; Jie, Zuliang; Hou, Lifei et al. (2015) IL-33 promotes innate IFN-? production and modulates dendritic cell response in LCMV-induced hepatitis in mice. Eur J Immunol 45:3052-63
Sun, Jiaren; Rajsbaum, Ricardo; Yi, MinKyung (2015) Immune and non-immune responses to hepatitis C virus infection. World J Gastroenterol 21:10739-48
Zhao, Zhenyang; Xu, Pei; Jie, Zuliang et al. (2014) ?? T cells as a major source of IL-17 production during age-dependent RPE degeneration. Invest Ophthalmol Vis Sci 55:6580-9