title: Novel role of IL-13 in fibrosis induced by nonalcoholic steatohepatitis and its amelioration by IL-13R-directed cytotoxin in a rat model.
abstract: 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-13Ralpha2), which is colocalized with smooth muscle actin, whereas fatty liver and normal liver specimens do not express IL-13Ralpha2. HSCs engineered to overexpress IL-13Ralpha2 respond to IL-13 and induce TGFB1 promoter activity and TGF-beta1 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-13Ralpha2 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.
authors.affiliation: 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, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Toshio
authors.initials: T
authors.lastname: Fujisawa
authors.forename: Syed R
authors.initials: SR
authors.lastname: Husain
authors.forename: Mitomu
authors.initials: M
authors.lastname: Kioi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003603:Cytotoxins / Q000378:metabolism / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005098:Exotoxins / Q000502:physiology* / Q000627:therapeutic use*; D005234:Fatty Liver / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D005786:Gene Expression Regulation / Q000276:immunology; D055166:Hepatic Stellate Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018793:Interleukin-13 / Q000502:physiology* / Q000627:therapeutic use*; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D008103:Liver Cirrhosis / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D053660:Receptors, Interleukin-13 / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology* / Q000627:therapeutic use*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D003603:Cytotoxins; D005098:Exotoxins; C521502:IL13-PE38; D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D012333:RNA, Messenger; D053660:Receptors, Interleukin-13; D011993:Recombinant Fusion Proteins