Inflammasome-mediated regulation of hepatic stellate cells
| Autor: | Azuma Watanabe, Wajahat Z. Mehal, Ardeshir Z. Hashmi, Dawidson Assis Gomes, Fayyaz S. Sutterwala, Muhammad Nauman Jhandier, Jun Nagata, Richard A. Flavell, Muhammad A. Sohail, Yan Shi, Shamail Mahmood |
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| Rok vydání: | 2009 |
| Předmět: |
Liver Cirrhosis
Physiology Gene Expression Inositol 1 4 5-Trisphosphate Thioacetamide Biology Collagen Type I Mice Downregulation and upregulation Transforming Growth Factor beta Physiology (medical) NLR Family Pyrin Domain-Containing 3 Protein Hepatic Stellate Cells medicine Animals Humans Calcium Signaling Carbon Tetrachloride Actin Cell Line Transformed Inflammation Mice Knockout Platelet-Derived Growth Factor Hepatology Chemotaxis Gastroenterology Inflammasome Actins Uric Acid Cell biology CARD Signaling Adaptor Proteins Mice Inbred C57BL Liver and Biliary Tract Cytoskeletal Proteins Liver Biochemistry Cell culture Apoptosis Hepatic stellate cell Apoptosis Regulatory Proteins Carrier Proteins Chemotaxis assay medicine.drug |
| Zdroj: | American Journal of Physiology-Gastrointestinal and Liver Physiology. 296:G1248-G1257 |
| ISSN: | 1522-1547 0193-1857 |
| DOI: | 10.1152/ajpgi.90223.2008 |
| Popis: | 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 α-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. |
| Databáze: | OpenAIRE |
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