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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 296/6/G1248    most recent 90223.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Watanabe, A. Articles by Mehal, W. Z. PubMed PubMed Citation Articles by Watanabe, A. Articles by Mehal, W. Z.

LIVER AND BILIARY TRACT

Inflammasome-mediated regulation of hepatic stellate cells

Departments of ¹Digestive Disease and ²Immunobiology, Yale University, New Haven, Connecticut; ³Departments of Microbiology & Infectious Diseases and Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada; ⁴Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Brazil

Submitted 6 March 2008 ; accepted in final form 28 March 2009

The inflammasome is a cytoplasmic multiprotein complex that has recently been identified in immune cells as an important sensor of signals released by cellular injury and death. Analogous to immune cells, hepatic stellate cells (HSC) also respond to cellular injury and death. Our aim was to establish whether inflammasome components were present in HSC and could regulate HSC functionality. Monosodium urate (MSU) crystals (100 µg/ml) were used to experimentally induce inflammasome activation in LX-2 and primary mouse HSC. Twenty-four hours later primary mouse HSC were stained with -smooth muscle actin and visualized by confocal microscopy, and TGF-β and collagen1 mRNA expression was quantified. LX-2 cells were further cultured with or without MSU crystals for 24 h in a transwell chemotaxis assay with PDGF as the chemoattractant. We also examined inhibition of calcium (Ca²⁺) signaling in LX-2 cells treated with or without MSU crystals using caged inositol 1,4,5-triphosphate (IP₃). Finally, we confirmed an important role of the inflammasome in experimental liver fibrosis by the injection of carbon tetrachloride (CCl₄) or thioacetamide (TAA) in wild-type mice and mice lacking components of the inflammasome. Components of the inflammasome are expressed in LX-2 cells and primary HSC. MSU crystals induced upregulation of TGF-β and collagen1 mRNA and actin reorganization in HSCs from wild-type mice but not mice lacking inflammasome components. MSU crystals inhibited the release of Ca²⁺ via IP₃ in LX-2 cells and also inhibited PDGF-induced chemotaxis. Mice lacking the inflammasome-sensing and adaptor molecules, NLRP3 and apoptosis-associated speck-like protein containing CARD, had reduced CCl₄ and TAA-induced liver fibrosis. We concluded that inflammasome components are present in HSC, can regulate a variety of HSC functions, and are required for the development of liver fibrosis.

apoptosis-associated speck-like protein containing CARD; NLRP3