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.