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

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.
The Journal of Immunology (Impact Factor: 4.92). 11/2008; 181(7):4656-65. DOI: 10.4049/jimmunol.181.7.4656
Source: PubMed


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.

Download full-text


Available from: Syed R Husain, Dec 17, 2013
  • Source
    • "at IL - 10 and IL - 13 ( and IL - 4 in some models ) in NASH are increased in the late stages of progression , as reported by Shimamura et al . ( 2008 ) . M2 cytokines , especially IL - 4 and IL - 13 , were significantly elevated in fibrosis mediated by carbon tetra - chloride ( CCl 4 ) in the liver , a feature that is linked to end - stage NASH ( Shimamura et al . , 2008 ) . To show the later M2 polarization shift , we studied the M2 cytokine profiles in our models of NASH . Our results showed that IL - 4 and IL - 13 were significantly elevated in mice that were coexposed to the hepatotoxin BDCM and the high - fat diet ( Fig . 3A ) ( P , 0 . 001 ) ."
    [Show abstract] [Hide abstract]
    ABSTRACT: Activation of M1 macrophages in the nonalcoholic steatohepatitis (NASH) following several external or endogenous factors viz inflammatory stimuli, oxidative stress and cytokines are known. However, any direct role of oxidative stress in causing M1 polarization in NASH has been unclear. We hypothesized that CYP2E1-mediated oxidative stress causes M1 polarization in experimental NASH and NO donor administration inhibits CYP2E1 mediated inflammation with concomitant attenuation of M1 polarization. Since CYP2E1 takes center stage in these studies we use a toxin model of NASH which uses a ligand and a substrate of CYP2E1 for inducing NASH. Subsequently we use a methionine and choline deficient diet induced rodent NASH model where CYP2E1 role in disease progression has been shown. Results show that CYP2E1 causes M1 polarization bias that includes a significant increase in IL-1β and IL-12 in both models of NASH while CYP2E1 null mice or diallyl sulfide administration prevented it. Administration of GdCl3, a macrophage toxin attenuated both the initial M1 response and subsequent M2 response showing the observed increase in cytokine levels is primarily from macrophages. Based on the evidence of an adaptive NO increase, NO donor administration in vivo, that mechanistically inhibited CYP2E1 catalyzed oxidative stress during the entire study in NASH abrogated M1 polarization and NASH progression. The results obtained show the association of CYP2E1 in M1 polarization and that inhibition of CYP2E1 catalyzed oxidative stress by NO donor (DETA NONOate) can be a promising therapeutic strategy in NASH.
    Journal of Pharmacology and Experimental Therapeutics 10/2014; 352(1). DOI:10.1124/jpet.114.218131 · 3.97 Impact Factor
  • Source
    • "IL-13 is a Th2 effector cytokine that is produced mainly by activated Th2 cells, and is therefore involved in protective immunity against extracellular parasites like helminths but also allergic disorders.33 In the liver, IL-13 is associated with progression of fibrosis, as it can induce the production of collagen, TGFβ, and other fibrosis-associated genes in HSCs.37,38 Its role in chronic liver diseases has been most extensively studied in mice with S. mansoni infection leading to granuloma formation and subsequent fibrosis development in the liver. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Interleukins represent a class of immunomodulatory cytokines, small intercellular signaling proteins, that are critically involved in the regulation of immune responses. They are produced in large amounts by various cell types during inflammatory reactions, and the balance of cytokines determines the outcome of an immune response. Therefore, cytokines are regarded as interesting therapeutic targets for the treatment of patients with liver diseases. Mouse models provide a good tool for in vivo studies on cytokine function, as human and mouse cytokines share many homologies. Sophisticated mouse models either mimicking distinct pathological conditions or targeting cytokines and cytokine-signaling pathways in the liver or even in distinct cellular compartments have provided enormous insight into the different functions of interleukins during hepatic inflammation. Interleukins may have pro- as well as anti-inflammatory functions in chronic liver diseases, some interleukins even both, dependent on the inflammatory stimulus, the producing and the responding cell type. IL-17, for example, promotes hepatic fibrogenesis through activation of hepatic stellate cells and facilitates development of liver cancer through recruitment of myeloid-derived suppressor cells. IL-22, on the other hand, protects from development of fibrosis or steatohepatitis. IL-12 balances T-helper (Th)-1 and Th2 cell responses in infectious disease models. IL-13 and IL-33, two cytokines related to Th2 cells and innate lymphoid cells, promote fibrotic responses in the liver. IL-10 is the prototypic anti-inflammatory interleukin with tissue-protective functions during chronic liver injury and fibrogenesis. Despite its critical role for inducing the acute-phase response in the liver, IL-6 signaling is protective during fibrosis progression, but promotes hepatocellular carcinoma. Experimental studies in mice help to define the exact influence of a specific cytokine on the outcome of chronic liver diseases and to identify useful therapeutic targets.
    Clinical and Experimental Gastroenterology 09/2014; 7:297-306. DOI:10.2147/CEG.S43737
  • Source
    • "IL-13 is a Th2 cytokine that plays a central role in various inflammatory diseases [46]. IL-13 induces tissue fibrosis by stimulating and activating TGF-β1 and was shown to play a role in progression from NASH to fibrosis in a rat model fed a choline deficient diet[47]. However, no studies have evaluated levels at early stages of NAFLD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nonalchoholic fatty liver disease (NAFLD) is a problem of increasing prevalence and clinical significance worldwide and is associated with increased risk of development of end stage liver disease and cirrhosis, and can be complicated by hepatocellular carcinoma (HCC). NAFLD is characterized by physical and molecular changes in the liver microenvironment which include an influx of inflammatory cell populations, fibrosis, changes in gene expression, and cytokine production. To better understand changes to the liver in the setting of steatosis, we used a murine model of diet induced hepatic steatosis and corroborated our results with human patient samples of NAFLD. Among the cellular changes, we identified a significant increase in hepatocellular proliferation in the setting of steatosis as compared to controls. Analysis of inflammatory cell populations revealed increased infiltration of CD11b positive myeloid and CD3 positive lymphocytic cell populations in steatotic livers compared to normal livers. Resident Kupffer cells of the liver comprise the largest percentage of these myeloid cells and appear to be responsible for important cytokine alterations impacting proliferation of cells in the liver microenvironment. Significant alterations in cytokine profiles in the plasma and liver tissue lysates from normal and steatotic mice were detected including leptin, CXCL1, CXCL2, and CXCL16 that were further shown to directly increase hepatocyte proliferation in vitro. This increased hepatocellular proliferation and turnover in the setting of steatosis may play important roles in the progression and complications of NAFLD.
    PLoS ONE 09/2013; 8(9):e73054. DOI:10.1371/journal.pone.0073054 · 3.23 Impact Factor
Show more