Potential conflict of interest: Nothing to report.
Supporting evidence for natural killer T cell accumulation in progressive nonalcoholic fatty liver disease?†
Article first published online: 23 OCT 2009
Copyright © 2009 American Association for the Study of Liver Diseases
Volume 51, Issue 1, pages 345–346, January 2010
How to Cite
Syn, W.-K. and Oo, Y. H. (2010), Supporting evidence for natural killer T cell accumulation in progressive nonalcoholic fatty liver disease?. Hepatology, 51: 345–346. doi: 10.1002/hep.23404
- Issue published online: 23 DEC 2009
- Article first published online: 23 OCT 2009
- Accepted manuscript online: 23 OCT 2009 12:00AM EST
To the Editor:
In a recent article in HEPATOLOGY, Kremer et al. explored the association between steatosis, cytokines, and natural killer T (NKT) cell numbers. Elegant experiments suggest that increased interleukin-12 (IL12) secretion, in part by Kupffer cells, leads to NKT depletion in mice and humans with liver steatosis.1
Recent data suggests that steatosis (consisting mainly of triglycerides) per se is a benign condition and reflects the body's strategy to cope with excessive fatty acid flux.2 Progressive fatty liver disease that develops in a minority of individuals may stem from dysregulated repair responses.3 The hedgehog pathway has been shown to modulate such responses, and overactivation of the hedgehog pathway leads to fibrogenesis. Furthermore, exposure of primary liver NKT cells to increasing concentrations of Sonic hedgehog, a hedgehog ligand, promotes NKT cell viability and proliferation, and enhances IL13 (a T helper 2 [Th2]cytokine) secretion.4 Mice with excessive hedgehog signaling also harbor increased NKT cells and develop increased fibrosis in diet-induced nonalcoholic steatohepatitis (W. K. Syn et al., manuscript submitted). Indeed, Tajiri et al. noted increased NKT numbers among individuals with greater nonalcoholic steatohepatitis activity scores.5 In contrast to benign hepatic steatosis, there is increasing data supporting the concept that NKT cells accumulate with progressive fatty liver disease.
In this study, NKT cell depletion was associated with elevated IL12 levels; conversely, NKT population was preserved in IL12 knockout mice. As suggested, additional factors are likely to be involved in determining the size of the hepatic NKT population. For example, NKT cells express cysteine-X-cysteine receptor 3 (CXCR3) and CXCR6; recruitment of NKT cells in steatotic liver is likely to be regulated by their associated ligands. In addition, because NKT cell viability is modulated by IL15,6 it would be important to determine if expression of IL15 alters with steatosis.
Although IL12 depletion resulted in lower interferon-gamma (IFN-γ) and tumor necrosis factor-α messenger RNA (Th1 cytokines), and smaller, albeit significant, reductions in IL4 and IL10 (Th2 cytokines), there was no significant change in the degree of steatosis. Although data on fibrogenesis (Sirius Red staining or hydroxyproline measurements) were not presented, the current observations lend support to the concept that hepatic steatosis and fibrogenesis represent overlapping but dichotomous pathogenic mechanisms. Rats fed the choline-deficient L-amino acid–defined diet develop fibrosis, which was attenuated when treated with IL13 cytotoxins that target IL13 receptors.7 Because NKT cells are producers of IL13, it would be of interest to ascertain if IL12 knockout mice express different amounts of IL13.
Reductions in both NKT and NK cells occurred in choline-deficient–diet mice and individuals with hepatic steatosis. However, when choline-deficient–diet mice were inoculated with clodronate-containing liposomes, they exhibited four-fold reductions in NK cells (and lower IL12) while maintaining NKT numbers. In contrast, control-treated mice preserved their NK population (and increased IL12) while reducing NKT numbers (a reversal of NK: NKT ratios)1. NK cells secrete IFN-γ and have been shown to inhibit fibrosis.8 Future work is needed to delineate the relationship between NKT and NK populations in progressive liver disease and determine if different NKT subsets affect disease outcomes.
- 1Kupffer cell and interleukin-12 dependent loss of natural killer T cells in hepatosteatosis. HEPATOLOGY 2009; doi:10.1002/hep.23292., , , , , , et al.
- 2Apoptosis and cytokines in non-alcoholic steatohepatitis. Clin Liver Dis 2009; 13: 565–580., , .
- 3Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease. Gastroenterology 2009; 137: 1478–1488., , , , , , et al.
- 4Role for hedgehog pathway in regulating growth and function of invariant NKT cells. Eur J Immunol 2009; 39: 1879–1892., , , , , , et al.
- 5Role of liver-infiltrating CD3+CD56+ natural killer T cells in the pathogenesis of nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2009; 21: 673–680., , , .
- 6Interleukin 15: biology and relevance to human disease. Blood 2001; 97: 14–32., .
- 7Novel role of IL-13 in fibrosis induced by nonalcoholic steatohepatitis and its amelioration by IL-13R-directed cytotoxin in a rat model. J Immunol 2008; 181: 4656–4665., , , , , .
- 8Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC. J Hepatol 2006; 45: 60–71., , , , , , et al.
Wing-Kin Syn M.D.* , Ye Htun Oo M.D., * Gastroenterology Division, Duke University, Durham, NC, Centre for Liver Research, Institute of Biomedical Research, University of Birmingham, Birmingham, UK.