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Novel Role of IL-13 in Fibrosis Induced by Nonalcoholic Steatohepatitis and Its Amelioration by IL-13R-Directed Cytotoxin in a Rat Model

Takeshi Shimamura^*, Toshio Fujisawa^*, Syed R. Husain^*, Mitomu Kioi^*, Atsushi Nakajima and Raj K. Puri^*,1

^* Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, National Institutes of Health, Bethesda, MD 20892; and Gastroenterology Division, Yokohama City University Graduate School of Medicine, Yokohama, Japan

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-13R2), which is colocalized with smooth muscle actin, whereas fatty liver and normal liver specimens do not express IL-13R2. HSCs engineered to overexpress IL-13R2 respond to IL-13 and induce TGFB1 promoter activity and TGF-β1 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-13R2 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Raj K. Puri, Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, National Institutes of Health, Building 29B, Room 2NN20 HFM-735, 29 Lincoln Drive, Bethesda, MD 20892. E-mail address: raj.puri{at}fda.hhs.gov

² Abbreviations used in this paper: NASH, nonalcoholic steatohepatitis; HSC, hepatic stellate cell; -SMA, -smooth muscle actin; IL13-PE38, recombinant fusion protein IL-13 cytotoxin; CDAA, choline-deficient L-amino acid; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; CSAA, control (normal) choline-supplemented L-amino acid.