Novel role of IL-13 in fibrosis induced by nonalcoholic steatohepatitis and its amelioration by IL-13R-directed cytotoxin in a rat model.
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.
Shimamura
Takeshi
T
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.
Fujisawa
Toshio
T
Husain
Syed R
SR
Kioi
Mitomu
M
Nakajima
Atsushi
A
Puri
Raj K
RK
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
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