Innate Immunity In the Liver

Zhiping Li, Anna Mae Diehl

Disclosures

Curr Opin Gastroenterol. 2003;19(6) 

In This Article

Hepatic Innate Immune System, Chronic Inflammation, and Insulin Resistance

The aforementioned studies clearly demonstrate that, in ob/ob mice, altered neurotransmitter signaling causes abnormality of hepatic innate immune system. This in turn causes Th-1 polarization of cytokine-producing cells with increased IFN-γ and TNF-α expression. This microenvironment favors the perpetuation of inflammatory signals. Sustained activation of inflammatory kinases, including Jun N-terminal kinase (JNK)[40*] and inhibitor kappa beta kinase (IKK-β),[41,42] in turn was recently found to cause cellular insulin resistance. The latter information identifies a potential mechanism for hepatic insulin resistance in leptin-deficient mice because both kinases are targets for TNF-α-initiated activation.[43] Others have already reported that breeding ob/ob mice with mice that are genetically deficient in TNF function generates offspring with improved systemic sensitivity to insulin.[44] To evaluate the role of TNF-α in hepatic insulin resistance, we treated adult ob/ob mice with vehicle or neutralizing anti-TNF antibodies for 1 month and compared hepatic activities of JNK and IKK-β in the two groups.[45*] Inhibiting TNF-α significantly reduced the hepatic activities of both kinases, thereby supporting the concept that, in leptin-deficient mice, excessive TNF-α activity contributes to hepatic insulin resistance.

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