Journal
JOURNAL OF IMMUNOLOGY
Volume 181, Issue 7, Pages 4656-4665Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.181.7.4656
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Nonalcoholic steatohepatitis (NASH), the most common cause of chronic liver fibrosis, progresses to cirrhosis in up to 20% of patients. We report that hepatic stellate cells (HSC) in sinusoidal lesions of liver of patients with NASH express high levels of high-affinity IL-13R (IL-13R alpha 2), which is colocalized with smooth muscle actin, whereas fatty liver and normal liver specimens do not express IL-13R alpha 2. HSCs engineered to overexpress IL-13R alpha 2 respond to IL-13 and induce TGFBI promoter activity and TGF-beta 1 production. We also developed NASH in rats by feeding a choline-deficient L-amino acid diet. These rats developed liver fibrosis as assessed by H&E staining, Masson's trichrome and Sirius red staining, and hydroxyproline assays. Treatment of these rats with IL-13R-directed cytotoxin caused a substantial decline in fibrosis and liver enzymes without organ toxicity. These studies demonstrate that functional IL-13R alpha 2 are overexpressed in activated HSCs involved in NASH and that IL-13 cytotoxin ameliorates pathological features of NASH in rat liver, indicating a novel role of this cytotoxin in potential therapy.
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