Regulation of T cell-mediated hepatic inflammation by adiponectin and leptin.
Concanavalin A-induced hepatotoxicity was compared in lipodystrophic aP2-nSREBP-1c transgenic mice (LD mice) lacking adipose tissue, obese leptin-deficient ob/ob mice, and lean wild-type (WT) mice. Serum leptin and adiponectin were low in LD mice, whereas ob/ob mice had undetectable leptin, but high adiponectin. Protection from hepatotoxicity was observed in ob/ob, but not in LD mice, despite low cytokine levels and reduced T cell activation and hepatic natural killer T cells in both groups. Administration of adiponectin protected LD mice from hepatotoxicity without altering cytokine levels. In contrast, administration of leptin heightened disease susceptibility by restoring cytokine production. Neutralization of TNF alpha protected LD mice from liver damage. Increased in vivo susceptibility to the hepatotoxic effect of TNF alpha was observed in LD mice. In vitro, adiponectin protected primary hepatocytes from TNF alpha-induced death, whereas leptin had no protective effect. In conclusion, although leptin increases susceptibility to hepatotoxicity by regulating cytokine production and T cell activation, adiponectin protects hepatocytes from TNF alpha-induced death.
Sennello
Joseph A
JA
Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Fayad
Raja
R
Morris
Alison M
AM
Eckel
Robert H
RH
Asilmaz
Esra
E
Montez
Jason
J
Friedman
Jeffrey M
JM
Dinarello
Charles A
CA
Fantuzzi
Giamila
G
D052242:Adiponectin; D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000139:chemically induced; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D003208:Concanavalin A; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics; D006505:Hepatitis / Q000276:immunology*; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology; D020738:Leptin / Q000097:blood / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D008060:Lipodystrophy / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D009765:Obesity / Q000276:immunology; D051780:Sterol Regulatory Element Binding Protein 1; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D052242:Adiponectin; D022762:CCAAT-Enhancer-Binding Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A