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

Michael Kremer, Emmanuel Thomas, Richard J. Milton, Ashley W. Perry, Nico Van Rooijen, Michael D. Wheeler, Steven Zacks, Michael Fried, Richard A. Rippe, Ian N. Hines

Research output: Contribution to journalArticle

98 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)130-141
Number of pages12
JournalHepatology
Volume51
Issue number1
DOIs
StatePublished - Jan 1 2010
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology

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    Kremer, M., Thomas, E., Milton, R. J., Perry, A. W., Van Rooijen, N., Wheeler, M. D., Zacks, S., Fried, M., Rippe, R. A., & Hines, I. N. (2010). Kupffer cell and interleukin-12-dependent loss of natural killer T cells in hepatosteatosis. Hepatology, 51(1), 130-141. https://doi.org/10.1002/hep.23292