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: Takeshi Shimamura, Toshio Fujisawa, Syed R Husain, Mitomu Kioi, Atsushi Nakajima, Raj K Puri
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 181 Issue 7 Pg. 4656-65 (Oct 01 2008) ISSN: 1550-6606 [Electronic] United States
• PMID: 18802068 (Publication Type: Journal Article)

Chemical References

• Cytotoxins
• Exotoxins
• IL13-PE38
• Interleukin-13
• Interleukin-13 Receptor alpha2 Subunit
• RNA, Messenger
• Receptors, Interleukin-13
• Recombinant Fusion Proteins

Topics

• Animals
• Cell Line
• Cell Line, Tumor
• Cells, Cultured
• Cytotoxins (metabolism, therapeutic use)
• Disease Models, Animal
• Exotoxins (physiology, therapeutic use)
• Fatty Liver (immunology, metabolism, therapy)
• Gene Expression Regulation (immunology)
• Hepatic Stellate Cells (immunology, metabolism, pathology)
• Humans
• Interleukin-13 (physiology, therapeutic use)
• Interleukin-13 Receptor alpha2 Subunit (biosynthesis, genetics, physiology)
• Liver Cirrhosis (immunology, metabolism, therapy)
• Male
• RNA, Messenger (biosynthesis)
• Rats
• Rats, Inbred F344
• Receptors, Interleukin-13 (physiology)
• Recombinant Fusion Proteins (physiology, therapeutic use)
• Signal Transduction (immunology)