Expression of Interleukin-10 by in Vitro and in Vivo Activated Hepatic Stellate Cells

Wang, Saixi C.; Ohata, Mitsuru; Schrum, Laura W.; Rippe, Richard A.; Tsukamoto, Hidekazu

doi:10.1074/jbc.273.1.302

Cited by 147 publications

(114 citation statements)

References 40 publications

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“…Persistent activation of hepatic stellate cells, the main fibrinogenic cell type in the damaged liver, 33 leads to progressive fibrosis during chronic infection. 34 An antifibrotic activity of IL-10 has been suggested by studies of cultured hepatic stellate cells 35 and by animal models of liver injury, including exogenous IL-10 administration, 36 IL-10 knockout mice 37 and transgenic IL-10 expression in liver. 38 Therefore, attenuation of liver fibrosis in regions containing IL-10-expressing CD8 T cells may be directly related to the antifibrotic IL-10 activity.…”

Section: Discussionmentioning

confidence: 99%

Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection

et al. 2006

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CD8 T cell killing of hepatitis C virus (HCV)-infected hepatocytes is thought to contribute to liver damage during chronic HCV infection, whereas the participation of HCV-nonspecific immune cells is unclear. To visualize the spatial relationship of HCV-specific CD8 T cells with parenchymal target cells, and to examine their local functional activity in relation to hepatocellular necrosis and fibrosis, we used HLA tetramers and confocal microscopy in biopsies from 23 HLA-A2 or HLA-B7 patients with chronic HCV infection. Intrahepatic tetramer؉ (HCV-specific) CD8 T cells protected from hepatic necroinflammatory disease activity, independently of age, gender, viral load, and viral genotype. Indeed, tetramer؉ cells were scattered in the liver within regions of weak fibrosis (low laminin expression) and low hepatocellular apoptosis (TUNEL method), and expressed IL-10 but not IFN␥. By contrast, tetramer-negative CD8 T cells were associated with active necroinflammatory liver disease, colocalized with strong laminin expression and hepatocellular apoptosis, and expressed more frequently IFN␥ than IL-10. Overall, liver regions harboring HCV-specific CD8 T cells tended to be healthier than areas containing only inflammatory cells of undefined specificity. In conclusion, HCV-specific IL-10-producing CD8 T cells, although not cytotoxic and unable to control viral replication, can attenuate hepatocellular necrosis, liver fibrosis, and inflammation mediated by bystander T cells, and may thus represent antigen-induced regulatory CD8 T cells. Therapeutic modulation of the intrahepatic balance between specific and bystander CD8 T cells might be beneficial in patients with chronic hepatitis C. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/ index.html).

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Section: Discussionmentioning

confidence: 99%

Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection

et al. 2006

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“…The synthesized cDNA for COX-2, TNF-␣, and ␤-actin were amplified using specific sets of primers designed from published sequences. 31,32 Statistical Analysis. Statistical methods included the 2 test for qualitative data and the t test and nonparametric tests (Mann-Whitney) for quantitative data.…”

Section: Intercellular Adhesion Molecule-1 and ␤-Integrin Immunohistomentioning

confidence: 99%

Exacerbation of Alcoholic Liver Injury by Enteral Endotoxin in Rats

et al. 2000

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Increased gut permeability (leaky gut) and endotoxin-mediated Kupffer cell activation are proposed as the mechanisms of alcoholic liver injury. Although ethanol feeding is shown to sensitize the liver for injury induced by parental administration of lipopolysaccharide (LPS), how enteral LPS loading affects alcoholic liver injury is yet to be tested. The present study provides direct evidence for enhanced entrance to portal circulation of LPS enterally administered to the intragastric ethanol infusion model. Portal and systemic blood endotoxin levels increased to 43.0 ؎ 4.1 and 6.2 ؎ 4.3 pg/mL at 2 hours following enteral LPS administration (5 mg/kg) in alcohol-fed animals, while no such increases were observed in pair-fed controls. However, endotoxin levels in systemic blood of alcohol-fed rats were reduced to 0 to 1.5 pg/mL 16 hours after LPS administration. Development of effective therapies for alcoholic liver disease (ALD) depends on the understanding of the mechanisms that contribute to the disease process. Experimental and clinical findings to date suggest that endotoxin and proinflammatory cytokines constitute the main effector molecules in alcohol-induced liver injury. 1-5 Endotoxin (lipopolysaccharide [LPS]), a prominent agonist of Kupffer cells, interacts with its specific carrier, LPS-binding protein (LBP) to stimulate hepatic macrophages via binding of the LPS-LBP complex to the CD14 receptor. [6][7][8] This stimulation results in the release of proinflammatory mediators by the macrophages and consequent immunological and cytotoxic events leading to development of liver injury.In rats given continuous infusion of ethanol and a high-fat diet, focal hepatic inflammation and necrosis may be evident after 4 weeks 9 and are accompanied by the pretranslational induction of proinflammatory cytokine expression in Kupffer cells. 10 Hepatic expression of tumor necrosis factor ␣ (TNF-␣) mRNA is induced when pathological changes in the liver become evident. 11 Simultaneous increases in the plasma endotoxin level and mRNA expression of proinflammatory cytokines are noted in ethanol-fed rats. 12,13 Taken together, these results suggest that induction of progressive alcoholic liver injury may require increased plasma endotoxin levels as a mechanism of proinflammatory cytokine induction. In support of this notion, alcoholic patients with chronic liver disease exhibit increased intestinal permeability. 14,15 Patients with alcoholic cirrhosis have higher endotoxin levels than heavy drinkers without cirrhosis and healthy controls. 16 Peripheral blood mononuclear cells isolated from patients with alcoholic cirrhosis secrete more interleukin-6, interleukin-8, and TNF-␣ than those from healthy controls. 17,18 In the intragastric infusion model, plasma endotoxin levels and enhanced LBP and CD14 expression are correlated with the presence of liver necrosis, [19][20][21][22] and the treatment of the animals with lactobacillus 23 or antibiotics 24 ameliorates alcoholic liver injury. Furthermore, intestinal permeability is als...

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“…22 Activation of hepatic stellate cells was shown to cause autocrine expression of IL-10 resulting in a negative autoregulatory effect on collagen production. 23 In addition, clinical studies demonstrated that IL-10 reduces necroinflammatory activity and progression of fibrosis in patients with CHC 24,25 and downregulates collagen synthesis in skin fibroblasts. 26 IL-10 mediates its biological effects by binding to the IL-10 receptor, which is a hetero-tetramer consisting of two of each receptor chains (IL-10R1 (interleukin-10 receptor 1) and IL-10R2), which belong to class II cytokine receptor family.…”

Section: Introductionmentioning

confidence: 99%

Bi-allelic presence of the interleukin-10 receptor 1 G330R allele is associated with cirrhosis in chronic HCV-1 infection

et al. 2005

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Immune response to viral infection is an important determinant of liver injury in chronic hepatitis C (CHC). Experimental and clinical data suggest a protective role of interleukin-10 (IL-10) in hepatic fibrogenesis. The significance of two SNPs of the interleukin-10 receptor 1 (IL-10R1), S138G (SNP3) and G330R (SNP4) was investigated on (i) susceptibility to CHC, (ii) progression of hepatic fibrosis and (iii) response to interferon/ribavirin therapy. DNA and liver biopsies were obtained from 212 patients with HCV (hepatitis C virus)-genotype-1 infection. The allele frequencies were 0.17 for SNP3 and 0.33 for SNP4, both of which were indifferent from healthy controls (0.17 and 0.32, respectively). Stage 1 liver fibrosis was found in 22 cases (10.4%), stage 2 in 108 (50.9%), stage 3 in 27 (12.8%), and stage 4 (cirrhosis) in 55 (25.9%). An association was found between the SNP4 allele and the presence of cirrhosis (P ¼ 0.01). Homozygous SNP4 individual variants segregated within the cirrhosis group (P ¼ 0.03). We found neither an association with SNP3 nor with the necroinflammatory disease activity (as measured by ALT levels) nor with the response to antiviral therapy. Our work implies that IL-10R1 SNP4 is a recessively inherited risk factor for hepatic cirrhosis in HCV genotype-1 infection.

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Expression of Interleukin-10 by in Vitro and in Vivo Activated Hepatic Stellate Cells

Cited by 147 publications

References 40 publications

Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection

Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection

Exacerbation of Alcoholic Liver Injury by Enteral Endotoxin in Rats

Bi-allelic presence of the interleukin-10 receptor 1 G330R allele is associated with cirrhosis in chronic HCV-1 infection

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