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(American Journal of Pathology. 2006;169:2042-2053.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060081

Resistin as an Intrahepatic Cytokine

Overexpression during Chronic Injury and Induction of Proinflammatory Actions in Hepatic Stellate Cells

Cristiana Bertolani*, Pau Sancho-Bru{dagger}, Paola Failli{ddagger}, Ramon Bataller{dagger}, Sara Aleffi*, Raffaella DeFranco*, Benedetta Mazzinghi§, Paola Romagnani§, Stefano Milani§, Pere Ginés{dagger}, Jordi Colmenero{dagger}, Maurizio Parola||, Stefania Gelmini§, Roberto Tarquini*, Giacomo Laffi*, Massimo Pinzani*¶ and Fabio Marra*¶

From the Dipartimento di Medicina Interna,* Fisiopatologia Clinica,§ and Farmacologia Preclinica e Clinica,{ddagger} and the Center for Research, Transfer, and High Education DENOTHE, University of Florence, Florence, Italy; the Dipartimento di Medicina e Oncologia Sperimentale,|| University of Turin, Turin, Italy; and the Liver Unit,{dagger} Hospital Clinic, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain

Obesity and insulin resistance accelerate the progression of fibrosis during chronic liver disease. Resistin antagonizes insulin action in rodents, but its role in humans is still controversial. The aims of this study were to investigate resistin expression in human liver and to evaluate whether resistin may affect the biology of activated human hepatic stellate cells (HSCs), key modulators of hepatic fibrogenesis. Resistin gene expression was low in normal human liver but was increased in conditions of severe fibrosis. Up-regulation of resistin during chronic liver damage was confirmed by immunohistochemistry. In a group of patients with alcoholic hepatitis, resistin expression correlated with inflammation and fibrosis, suggesting a possible action on HSCs. Exposure of cultured HSCs to recombinant resistin resulted in increased expression of the proinflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, through activation of nuclear factor (NF)-{kappa}B. Resistin induced a rapid increase in intracellular calcium concentration, mainly through calcium release from intracellular inositol triphosphate-sensitive pools. The intracellular calcium chelator BAPTA-AM blocked resistin-induced NF-{kappa}B activation and monocyte chemoattractant protein-1 expression. In conclusion, this study shows a role for resistin as an intrahepatic cytokine exerting proinflammatory actions in HSCs, via a Ca2+/NF-{kappa}B-dependent pathway and suggests involvement of this adipokine in the pathophysiology of liver fibrosis.




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