Kupffer cell and interleukin‐12–dependent loss of natural killer T cells in hepatosteatosis

• Published in: Hepatology (Baltimore, Md.) Vol. 51; no. 1; pp. 130 - 141
• Main Authors: Kremer, Michael, Thomas, Emmanuel, Milton, Richard J., Perry, Ashley W., van Rooijen, Nico, Wheeler, Michael D., Zacks, Steven, Fried, Michael, Rippe, Richard A., Hines, Ian N.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-01-2010; Wiley; Wiley Subscription Services, Inc
• Subjects: Animals; Biological and medical sciences; Choline Deficiency - immunology; Cytokines; Fatty Liver - immunology; Fatty Liver - pathology; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Interferon-gamma - biosynthesis; Interleukin-12 - biosynthesis; Interleukin-12 - physiology; Kupffer Cells - immunology; Kupffer Cells - physiology; Liver - pathology; Liver cirrhosis; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Macrophages - metabolism; Male; Medical sciences; Mice; Natural Killer T-Cells - immunology; Rodents; T cell receptors; Tumor Necrosis Factor-alpha - biosynthesis; Tumor necrosis factor-TNF; Natural killer cell; Kupffer cell; Interleukin 12; Gastroenterology
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.23292

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.)