Cells In Alcoholic Liver Disease Research Articles

Recent Insights Into the Role of Immune Cells in Alcoholic Liver Disease.

Accumulating clinical and experimental evidences have demonstrated that both innate and adaptive immunity are involved in the pathogenesis of alcoholic liver disease (ALD), in which the role of immunity is to fuel the inflammation and to drive the progression of ALD. Various immune cells are implicated in the pathogenesis of ALD. The activation of innate immune cells induced by alcohol and adaptive immune response triggered by oxidative modification of hepatic constituents facilitate the persistent hepatic inflammation. Meanwhile, the suppressed antigen-presenting capability of various innate immune cells and impaired function of T cells may consequently lead to an increased risk of infection in the patients with advanced ALD. In this review, we summarized the significant recent findings of immune cells participating in ALD. The pathways and molecules involved in the regulation of specific immune cells, and novel mediators protecting the liver from alcoholic injury via affecting these cells are particularly highlighted. This review aims to update the knowledge about immunity in the pathogenesis of ALD, which may facilitate to enhancement of currently available interventions for ALD treatment.

Alcohol-induced miR-155 and HDAC11 inhibit negative regulators of the TLR4 pathway and lead to increased LPS responsiveness of Kupffer cells in alcoholic liver disease.

Inflammation promotes the progression of alcoholic liver disease. Alcohol sensitizes KCs to gut-derived endotoxin (LPS); however, signaling pathways that perpetuate inflammation in alcoholic liver disease are only partially understood. We found that chronic alcohol feeding in mice induced miR-155, an inflammatory miRNA in isolated KCs. We hypothesized that miR-155 might increase the responsiveness of KCs to LPS via targeting the negative regulators of LPS signaling. Our results revealed that KCs that were isolated from alcohol-fed mice showed a decrease in IRAK-M, SHIP1, and PU.1, and an increase in TNF-α levels. This was specific to KCs, as no significant differences were observed in these genes in hepatocytes. We found a causal effect of miR-155 deficiency on LPS responsiveness, as KCs that were isolated from miR-155 KO mice showed a greater induction of IRAK-M, SHIP1, and suppressor of cytokine signaling 1 after LPS treatment. C/EBPβ, a validated miR-155 target, stimulates IL-10 transcription. We found a higher induction of C/EBPβ and IL-10 in KCs that were isolated from miR-155 KO mice after LPS treatment. Gain- and loss-of-function studies affirmed that alcohol-induced miR-155 directly regulates IRAK-M, SHIP1, suppressor of cytokine signaling 1, and C/EBPβ, as miR-155 inhibition increased and miR-155 overexpression decreased these genes in LPS or alcohol-pretreated wild-type KCs. HDAC11, a regulator of IL-10, was significantly increased and IL-10 was decreased in KCs that were isolated from alcohol-fed mice. Functionally, knockdown of HDAC11 with small interfering RNA resulted in an IL-10 increase in LPS or alcohol-pretreated Mϕ. We found that acetaldehyde and NF-κB pathways regulate HDAC11 levels. Collectively, our results indicate that the alcohol-induced responsiveness of KCs to LPS, in part, is governed by miR-155 and HDAC11.

Characterizations of mucosal associated invariant T cells in alcoholic liver disease

Abstract The liver is a critical immunological site for chronic alcohol consumption as it filters various antigens activating both innate and adaptive responses. The pathogenesis of alcoholic liver disease (ALD) in human is not clear in terms of the specific role of immune cell population. Mucosal associated invariant T (MAIT) cells are found to be abundant in the mucosal organs, especially within the liver organ in which the cells comprise up to 50 % of T cells. Here, we show that the percentage of circulating MAIT cells is severely reduced in ALD patients (p=0.0028), including patients with steatohepatitis (ASH, n=20), steatohepatitis with cirrhosis (ASHAC, n=15) and cirrhosis (AC, n=12), compared to age-matched healthy donors (HD, n=8). Moreover, compared to non-liver disease group, MAIT cells are depleted among liver infiltrating lymphocytes in ASH (p=0.0276) and ASHAC (p=0.0049) patients, whereas that of AC group is recovered. Although the percentage of MAIT cells is decreased, the cells display increased expression level of activation markers. Pro-inflammatory cytokines such as IL-17A and MIP-1 beta are up-regulated in ASH and ASHAC patients by PMA/Ionomycin stimulation. In addition, Perforin and Granzyme B, which are cytotoxic markers in granule, are significantly increased in both peripheral blood and liver of ASHAC group. Taken together, our results suggest that activated MAIT cell population in the liver may contribute to the pathogenesis of ALD.

Metabolic danger signals, uric acid and ATP, mediate inflammatory cross-talk between hepatocytes and immune cells in alcoholic liver disease.

Inflammation defines the progression of ALD from reversible to advanced stages. Translocation of bacterial LPS to the liver from the gut is necessary for alcohol-induced liver inflammation. However, it is not known whether endogenous, metabolic danger signals are required for inflammation in ALD. Uric acid and ATP, 2 major proinflammatory danger signals, were evaluated in the serum of human volunteers exposed to a single dose of ethanol or in supernatants of primary human hepatocytes exposed to ethanol. In vitro studies were used to evaluate the role of uric acid and ATP in inflammatory cross-talk between hepatocytes and immune cells. The significance of signaling downstream of uric acid and ATP in the liver was evaluated in NLRP3-deficient mice fed a Lieber-DeCarli ethanol diet. Exposure of healthy human volunteers to a single dose of ethanol resulted in increased serum levels of uric acid and ATP. In vitro, we identified hepatocytes as a significant source of these endogenous inflammatory signals. Uric acid and ATP mediated a paracrine inflammatory cross-talk between damaged hepatocytes and immune cells and significantly increased the expression of LPS-inducible cytokines, IL-1β and TNF-α, by immune cells. Deficiency of NLRP3, a ligand-sensing component of the inflammasome recognizing uric acid and ATP, prevented the development of alcohol-induced liver inflammation in mice and significantly ameliorated liver damage and steatosis. Endogenous metabolic danger signals, uric acid, and ATP are involved in inflammatory cross-talk between hepatocytes and immune cells and play a crucial role in alcohol-induced liver inflammation.

Roles of Kupffer Cells in Alcoholic Liver Disease

This article summarizes presentations at the 2004 International Society for Biomedical Research on Alcoholism held in Heidelberg/Mannheim, Germany. The organizers and chairpersons were Yoshiyuki Takei and Gavin E Arteel. The presentations were on 1) Kupffer cell-derived mediators involved in alcoholic liver disease: reactive oxygen and nitrogen species, by Gavin E. Arteel; 2) Kupffer cell-derived mediators in alcoholic liver disease: tumor necrosis factor-a, by Laura E. Nagy; 3) metformin prevents acute alcohol-induced fat accumulation in mouse liver, by Ina Bergheim; 4) gender difference in alcoholic liver disease, by Nobuyuki Enomoto; and 5) Kupffer cells as a therapeutic target of alcoholic liver disease, by Yoshiyuki Takei.

The role of kupffer cell oxidant production in early ethanol-induced liver disease 1,2

Considerable evidence for a role of Kupffer cells in alcoholic liver disease has accumulated and they have recently been shown to be a predominant source of free radicals. Several approaches including pharmacological agents, knockout mice, and viral gene transfer have been used to fill critical gaps in understanding key mechanisms by which Kupffer cell activation, oxidant formation, and cytokine production lead to liver damage and subsequent pathogenesis. This review highlights new data in support of the hypothesis that Kupffer cells play a pivotal role in hepatotoxicity due to ethanol by producing oxidants via NADPH oxidase.

INCREASED MONOCYTE MCP-1 PRODUCTION IN ACUTE ALCOHOLIC HEPATITIS

Monocyte chemoattractant protein-1 (MCP-1) is a potent mononuclear cell-specific chemotactic protein. MCP-1 is a candidate chemoattractant for activation and hepatic infiltration of mononuclear cells in alcoholic hepatitis (AH). Blood was collected from 15 patients with AH (mean bilirubin 17.6±3.5mg/dl; normal 0.2–1.0mg/dl) on admission and at time points for up to 6 months. Peripheral blood monocytes were isolated and MCP-1 production assessed by measuring MCP-1 concentrations in monocyte culture supernatants after overnight (20h) incubation. Monocytes from normal subjects did not product detectable MCP-1 unless stimulated with endotoxin (LPS;5μg/ml). The mean level of constitutive MCP-1 from AH patient monocytes was 4694±2432pg/ml20h on admission. The mean MCP-1 level for LPS-treated monocytes was 4903±1540pg/ml20h for normal subjects and was significantly elevated in AH patients to 11589±3266pg/ml/20h. AH patient monocyte MCP-1 production was decreased in vitro when monocytes were treated with N-acetylcysteine (5mM) and also decreased over the 6-month study as the patients improved clinically. MCP-1 plasma levels were below the detection limits of the assay used in both AH patients and normal subjects. Thus, monocytes from AH patients not only constitutively product MCP-1, but also produce higher levels of MCP-1 with endotoxin stimulation. Further studies are needed to clarify the role of MCP-1 in the activation and hepatic infiltration of mononuclear cells in alcoholic liver disease.

Hepatic sinusoidal endothelial cells in alcoholic liver disease — Phenotypic changes and basement membrane protein formation

Hepatic sinusoidal endothelial cells in alcoholic liver disease — Phenotypic changes and basement membrane protein formation

アルコール性肝障害におけるアセトアルデヒド結合細胞に対する特異的キラーＴ細胞の証明

アルコール性肝障害におけるアセトアルデヒド結合細胞に対する特異的キラーＴ細胞の証明

Spontaneous IgA synthesis by blood mononuclear cells in alcoholic liver disease.

Changes in the concentration and composition of serum immunoglobulin A (IgA) and deposits of IgA in tissues are well-known characteristics of alcoholic liver disease. We investigated whether these changes also accompany IgA synthesis by peripheral blood mononuclear cells (MNC), by counting immunoglobulin-producing cells using a solid-phase enzymatic 'spot' test, and by analysis of immunoglobulin content in lysed cells with culture supernatant using conventional enzymatic methods. Patients with alcoholic liver disease exhibited a significantly higher number of spontaneously IgA-producing cells than did normal healthy controls (1.7 X 10(6) cells/blood and 0.5 X 10(6) cells/blood, respectively, P less than 0.01). The IgA content of MNC directly after isolation was also higher (38 and 13 ng/10(6) MNC, respectively, P less than 0.01), as was the IgA production during an unstimulated 6-day culture period (520 and 95 ng/10(6) MNC put into culture, respectively, P less than 0.001). The spontaneously IgA-producing cells assessed directly after isolation of mononuclear cells correlated with the IgA production during an unstimulated culture (P less than 0.01). We conclude that in alcoholic liver disease, B lymphocytes circulate which may have been activated in vivo.

Histochemical characteristics of fat-storing cells in alcoholic liver disease: a study by the gold chloride method using needle biopsy specimens of the liver.

To evaluate the relationship between fat-storing cells and fibrosis of the liver in alcoholic liver disease, the characteristics of fat-storing cells were studied by light microscopy with a modification of Kupffer's gold chloride method. Liver biopsy specimens were obtained at laparoscopy with a Trucut needle from 59 patients with alcoholic liver disease, 10 with no hepatic fibrosis, 18 with mild fibrosis, 18 with moderate fibrosis, and 13 with liver cirrhosis. These specimens were divided into three classes (weak, moderate, and strong) with respect to the response of fat-storing cells to the gold chloride reaction, which indicates the amount of vitamin A contained in fat-storing cells. It was found that in alcoholic liver disease the gold chloride reaction became weaker as hepatic fibrosis progressed (P less than 0.001). By contrast, no significant association was observed between the gold chloride reaction and the degree of hepatic fibrosis in 74 specimens from patients with nonalcoholic liver disease. These results show that in alcoholic liver disease hepatic fibrosis is characterized histochemically by the reduced response of fat-storing cells to the gold chloride reaction. The role of the change in fat-storing cells in alcoholic liver disease remains to be elucidated.