Murine leptin deficiency alters Kupffer cell production of cytokines that regulate the innate immune system.
OBJECTIVE
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.
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005234:Fatty Liver / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007107:Immune System / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis*; D019409:Interleukin-15 / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000276:immunology; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D020738:Leptin / Q000172:deficiency / Q000235:genetics* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains
D019409:Interleukin-15; D020738:Leptin; D008070:Lipopolysaccharides; D018664:Interleukin-12