Background & Aims: ob/ob mice are used to study the mechanisms that regulate the progression from steatosis to nonalcoholic steatohepatitis. The livers of ob/ob mice are depleted of CD4-positive natural killer cells, components of the innate immune system that induce anti-inflammatory cytokines. Although this may explain the sensitivity of fatty livers to lipopolysaccharide, why such hepatic CD4-positive natural killer cell depletion occurs is uncertain. Because leptin regulates macrophages, our hypothesis is that leptin deficiency alters Kupffer cell production of cytokines that inhibit (e.g., interleukin [IL]-12) or enhance (e.g., IL-15) hepatic CD4-positive natural killer cell viability. Methods: Kupffer cell cytokine production and the hepatic content of CD4-positive natural killer cells were compared in ob/ob and lean mice. ob/ob mice were then treated with IL-15 or leptin to determine whether either factor improved their immunologic abnormalities. Results: Compared with control Kupffer cells, ob/ob Kupffer cells produced less IL-15 basally and more IL-12 after lipopolysaccharide stimulation. Treatment of ob/ob mice with IL-15 for 1 week normalizes their hepatic CD4-positive natural killer cell content. Leptin increases the hepatic expression of IL-15 in ob/ob mice and partially replenishes their hepatic CD4-positive natural killer cells. Conclusions: Leptin deficiency increases hepatic IL-12 and reduces hepatic IL-15 expression. The abnormal production of these Kupffer cell factors promotes hepatic CD4-positive natural killer cell depletion in ob/ob livers.
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