Kupffer Cell and Interleukin-12–Dependent Loss of Natural... : Hepatology (original) (raw)

Steatohepatitis/Metabolic Liver Disease

Kupffer Cell and Interleukin-12–Dependent Loss of Natural Killer T Cells in Hepatosteatosis

Kremer, Michael1,2; Thomas, Emmanuel3; Milton, Richard J.1; Perry, Ashley W.1; van Rooijen, Nico4; Wheeler, Michael D.1; Zacks, Steven3; Fried, Michael3; Rippe, Richard A.3; Hines, Ian N.1,3,*

1_Center for Alcohol Studies, University of North Carolina at Chapel Hill, NC_

2_Department of Surgery, University of Heidelberg, Germany_

3_Department of Medicine, University of North Carolina at Chapel Hill, NC_

4_Department of Cell Biology, Free University, Amsterdam, Netherlands_

*Address reprint requests to: Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, 7336 Medical Biomolecular Research Building, Campus Box #7032, Chapel Hill, NC 27599. Email:[email protected]; fax: (919) 843-6899

Received 6 October 2008; Accepted 18 August 2009

Published online 9 September 2009 in Wiley InterScience (www.interscience.wiley.com).

Supported by grants from the National Institute for Alcohol Abuse and Alcoholism, AA016563 (to I.N.H.) and AA014243 (to R.A.R.) and by the ABMRF/The Foundation for Alcohol Research (to I.N.H.).

Potential conflict of interest: Nothing to report.

Additional Supporting Information may be found in the online version of this article.

Abstract

Hepatosteatosis is associated with increased expression of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-12, major T helper (Th) 1 cytokines, and reduced hepatic natural killer T (NKT) cell numbers. The relationship between lipid accumulation, cytokine expression, and hepatic NKT cells is not known. This study was conducted to assess the role of IL-12 in the development of hepatic steatosis and its potential impact on liver NKT cells. Male C57Bl/6 wildtype (WT) and IL-12-deficient (IL-12−/−) mice were fed a choline-deficient diet (CDD) for 0, 10, or 20 weeks. CDD led to marked hepatosteatosis, reduced hepatic but not splenic NKT cell numbers and function, and increased hepatic expression of the Th1-type cytokines IL-12, interferon gamma (IFN-γ), and TNF-α in WT mice. The absence of IL-12 resulted in similar CDD-induced hepatosteatosis, but preserved hepatic NKT cells and significantly reduced hepatic IFN-γ and TNF-α expression. Treatment of CDD-fed mice with lipopolysaccharide led to a significant increase in hepatic IL-12 expression, and Kupffer cell (KC) depletion reduced liver IL-12 expression and restored NKT cells in CDD-induced fatty liver. Interestingly, KCs from CDD-fed mice failed to produce increased quantities of IL-12 upon activation in vitro when compared to similarly treated KCs from control fed mice, suggesting that secondary factors in vivo promote heightened IL-12 production. Finally, human livers with severe steatosis showed a substantial decrease in NKT cells. Conclusion: Hepatosteatosis reduces the numbers of hepatic NKT cells in a KC-and IL-12-dependent manner. Our results suggest a pivotal and multifunctional role of KC-derived IL-12 in the altered immune response in steatotic liver, a process that is likely active within human nonalcoholic fatty liver disease. (Hepatology 2010;51:130–141.)