Monocyte SIRT7 and Cytokine Expression in Alcoholic Hepatitis

Abstract

Abstract Background: Acute alcoholic hepatitis (AH) is a distinct form of alcoholic liver disease characterized by acute jaundice and hepatic and systemic inflammation. Heavy alcohol consumption is well-tolerated by most individuals. Only a minority of heavy drinkers experience an episode of acute AH. Variation in resident and infiltrating macrophage immune response is believed to underly the variable penetrance observed in acute alcoholic hepatitis. Here we examine the relationship of SIRT7 and inflammatory cytokine expression in peripheral blood monocytes in alcoholic hepatitis. Objectives: The objectives of this study were to: 1) determine the relationship between p-FOXO3, SIRT7, and inflammatory cytokine response in circulating monocytes in patients with acute AH; 2) assess the association between clinical outcomes, inflammatory cytokine expression levels, and SIRT7; and 3) to compare levels of p-FOXO3, SIRT7, and inflammatory cytokine expression in patients at varying risk for AH. Methods: Peripheral blood monocytes were isolated from patients with acute AH and various control groups and were treated with 100ng/mL lipopolysaccharide (LPS). Relative expression of SIRT7, TNFα, IL-6, IL-10, ICAM1, and CCL2 were measured using reverse transcriptase real-time PCR. SIRT7 and cytokine expression data were assessed for correlation with model for end-stage liver disease (MELD) score and Maddrey Discriminant Function (MDF) score. Results: Ninety-nine subjects, including 22 with acute AH were enrolled. There was no significant difference in LPS-stimulated SIRT7 expression among patients with AH, healthy controls, healthy drinkers (alcohol control), and sepsis patients (inflammatory control). In patients with AH, SIRT7 expression is correlated with CCL2 expression (R=0.689, P=0.0004). SIRT7 expression is not correlated with TNFα, IL6, ICAM1, IL10, MELD score, or MDF score. LPS-stimulated levels of SIRT7 were not significantly different among patients hypothesized to be at low risk (healthy controls & healthy drinkers), medium risk (alcoholic & non-alcoholic cirrhosis), or high risk (previous history of AH) of developing acute AH. Conclusions: SIRT7 mRNA expression does not reflect monocyte or clinical phenotype. Further studies assessing SIRT7 and FOXO3 protein levels are needed.