Innate immunity and cytokines in liver disease: The liver is an organ with strong innate immunity, which plays an important role in host defense against microbial infection and tumor transformation. Emerging evidence suggests that innate immunity as well as a variety of cytokines produced by innate immune cells also contribute to the pathogenesis of acute and chronic liver diseases. Our laboratory has been actively studying the role of innate immunity and its associated cytokines in liver injury and repair. During the fiscal year, we have demonstrated (1) that invariant NKT cell activation induces neutrophil accumulation and hepatitis and (2) that IFN- inhibits liver progenitor cell proliferation in HBV-infected patients and in 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-fed mice. Invariant NKT cell activation induces neutrophil accumulation and hepatitis: Opposite regulation by IL-4 and IFN-gamma: Alpha-Galactosylceramide (alpha-Galcer), a specific agonist for invariant natural killer T (iNKT) cells, is being evaluated in clinical trials for the treatment of viral hepatitis and liver cancer. However, the results from alpha-Galcer treatment are mixed, partially because of the variety of cytokines produced by activated iNKT cells that have an unknown synergistic effect on the progression of liver disease. It is well documented that injection of alpha-Galcer induces mild hepatitis with a rapid elevation in the levels of interleukin (IL)-4 and a delayed elevation in the levels of interferon-gamma (IFN-gamma), and both of these cytokines are thought to mediate many functions of iNKT cells. Surprisingly, during this reporting period, we have demonstrated that genetic deletion of both IL-4 and IFN-gamma aggravated, rather than abolished, alpha-Galcer-induced iNKT hepatitis. Moreover, genetic ablation of IL-4, the IL-4 receptor, or its downstream signaling molecule signal transducer and activator of transcription (STAT)6 ameliorated alpha-Galcer-induced neutrophil infiltration, liver injury, and hepatitis. In contrast, genetic deletion of IFN-gamma, the IFN-gamma receptor, or its downstream signaling molecule STAT1 enhanced liver neutrophil accumulation, thereby exacerbating liver injury and hepatitis. Moreover, depletion of neutrophils eradicated alpha-Galcer-induced liver injury in wild-type, STAT1 knockout, and IFN-gamma knockout mice. Conclusion: Our results propose a model in which activated iNKT cells rapidly release IL-4, which promotes neutrophil survival and hepatitis but also sequentially produce IFN-gamma, which acts in a negative feedback loop to ameliorate iNKT hepatitis by inducing neutrophil apoptosis. Thus, modification of iNKT production of IL-4 and IFN-gamma may have the potential to improve the efficacy of alpha-Galcer in the treatment of liver disease. IFN-gamma inhibits liver progenitor cell proliferation in HBV-infected patients and in 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-fed mice. Proliferation of liver progenitor cells (LPCs) is associated with inflammation and fibrosis in chronic liver diseases. However, how inflammation and fibrosis affect LPCs remains obscure. During this reporting period, we examined the role of interferon (IFN)-gamma, an important pro-inflammatory and anti-fibrotic cytokine, in LPC expansion in HBV-infected patients and in mice challenged with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- or choline-deficient, ethionine-supplemented (CDE) diet as well as in primary LPCs and LPC cell line. We have demonstrated that the CK19 staining scores correlated with inflammation and fibrosis grades in the livers from 110 HBV-infected patients. Nine-month IFN-gamma treatment decreased LPC numbers, inflammation, and fibrosis in these HBV-infected patients. Similarly, a two-week IFN-gamma treatment also decreased LPC activation in DDC-treated mice. Disruption of IFN-gamma or its signaling components (e.g., IFNGR, STAT1, and IRF-1) increased LPC proliferation and liver fibrosis in DDC-fed mice. In contrast, deletion of IFN-gamma did not increase, but rather slightly reduced LPC proliferation in CDE-fed mice. In vitro, IFN-gamma attenuated proliferation of the LPC cell line BMOL and of primary LPCs from wild type mice, but not STAT1-/- or IRF-1-/- mice. Furthermore, co-culture assays suggest that IFN-gamma can indirectly promote LPC proliferation via the activation of macrophages but attenuate it via the inhibition of hepatic stellate cells. In conclusion: IFN-gamma inhibits LPC expansion via the direct inhibition of LPC proliferation and indirect attenuation of liver fibrosis in the DDC model, but it may also enhance LPC expansion via the promotion of inflammation in the CDE model;thereby playing dual roles in regulating LPC proliferation in vivo.

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National Institute on Alcohol Abuse and Alcoholism
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Kwon, Hyo-Jung; Won, Young-Suk; Park, Ogyi et al. (2014) Aldehyde dehydrogenase 2 deficiency ameliorates alcoholic fatty liver but worsens liver inflammation and fibrosis in mice. Hepatology 60:146-57
Kwon, Hyo-Jung; Won, Young-Suk; Park, Ogyi et al. (2014) Opposing effects of prednisolone treatment on T/NKT cell- and hepatotoxin-mediated hepatitis in mice. Hepatology 59:1094-106
Zhao, Juanjuan; Zhang, Zheng; Luan, Yan et al. (2014) Pathological functions of interleukin-22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment. Hepatology 59:1331-42
Mukhopadhyay, Partha; Rajesh, Mohanraj; Cao, Zongxian et al. (2014) Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis. Hepatology 59:1998-2009
Feng, Dechun; Wang, Yan; Wang, Hua et al. (2014) Acute and chronic effects of IL-22 on acetaminophen-induced liver injury. J Immunol 193:2512-8
Wang, Hua; Feng, Dechun; Park, Ogyi et al. (2013) Invariant NKT cell activation induces neutrophil accumulation and hepatitis: opposite regulation by IL-4 and IFN-?. Hepatology 58:1474-85
Weng, Hong-lei; Feng, De-chun; Radaeva, Svetlana et al. (2013) IFN-ýý inhibits liver progenitor cell proliferation in HBV-infected patients and in 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-fed mice. J Hepatol 59:738-45
Gao, Bin; Radaeva, Svetlana; Park, Ogyi (2009) Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases. J Leukoc Biol 86:513-28
Pan, Hao; Shen, Zhoujun; Mukhopadhyay, Partha et al. (2009) Anaphylatoxin C5a contributes to the pathogenesis of cisplatin-induced nephrotoxicity. Am J Physiol Renal Physiol 296:F496-504
Lafdil, Fouad; Wang, Hua; Park, Ogyi et al. (2009) Myeloid STAT3 Inhibits T Cell-Mediated Hepatitis by Regulating T Helper 1 Cytokine and Interleukin-17 Production. Gastroenterology :

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