Innate immunity in the liver.
OBJECTIVE
The liver is constantly exposed to large varieties of antigens that are derived from the gastrointestinal tract, including dietary antigens, pathogens, and toxins. Its function as a major immune organ is now being appreciated. The liver lymphocyte population is enriched in macrophages (ie, Kupffer cells), natural killer and natural killer T cells, which constitute the innate immune system. This review will focus on recent advances in the understanding of mechanisms that regulate the hepatic innate immune system because the innate immune system may mediate many chronic liver diseases, including nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis.


RESULTS
Hepatic natural killer T cells modulate liver injury by balancing local production of proinflammatory (Th-1) and antiinflammatory (Th-2) cytokines. Hepatic natural killer T cell depletion leads to Th-1 polarization of hepatic cytokine production, increasing tumor necrosis factor alpha and interferon gamma. This potentates lipopolysaccharide-induced hepatotoxicity. The hepatic natural killer T cells themselves are regulated by Kupffer-cell-produced cytokines, dietary factors, and certain neurotransmitters, such as norepinephrine. In leptin-deficient ob/ob mice, an animal model for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, insufficient norepinephrine increases hepatic natural killer T cell apoptosis, depleting hepatic natural killer T cells and inducing proinflammatory cytokine polarization. This contributes to chronic inflammation, increased lipopolysaccharide-induced hepatotoxicity, and insulin resistance in ob/ob mice.


CONCLUSIONS
Assuming that defects in the hepatic innate immune system that promote Th-1 cytokine polarization are common pathogenic mechanisms for hepatic insulin resistance and nonalcoholic steatohepatitis, therapies that inhibit inflammatory activity may be beneficial for these disorders.
Li
Zhiping
Z
Department of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205, USA.
Diehl
Anna Mae
AM