Chronic alcohol-induced liver disease inhibits dendritic cell function

Abstract

Background/Aims We have compared dendritic cell (DC) function derived from the alcoholic liver disease (ALD) sensitive Long–Evans (LE) and resistant Fischer rat strains to determine if the influence of ethanol on DCs was dependent on ALD. Methods The LE and Fischer rats were fed an ethanol-containing or isocaloric control liquid diet for 8 weeks and comparisons were made to LE rats injected with thioacetamide as a liver disease control. DCs were isolated from the spleen after expansion with human Fms-like tyrosine kinase receptor 3 ligand plasmid. Maturation markers CD86, CD80, CD40 and MHC-II were analysed by flow cytometry with or without lipopolysaccharide and poly I:C stimulation. Production of tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin (IL)-12p40 and IL-10 cytokines and the antigen presentation ability of DCs was determined. Results Only LE rats developed ALD characterized by liver injury, elevated alanine aminotransferase levels and steatosis; CD86 and CD40 expression was decreased in LE but not Fischer rats. Reduced TNF-α, IFN-γ, IL-12, proinflammatory and enhanced IL-10 cytokine production was found in DCs isolated from ethanol-fed LE but not Fischer rats. Allostimulatory activity was reduced in LE compared with the Fischer strain. In contrast, DCs isolated from thioacetamide-induced liver damage displayed a reduction only in IL-12p40; TNF-α, IL-10 and IFN-α production as well as antigen presenting ability remained intact compared with controls. Conclusions ALD sensitive LE rats exhibited characteristics of a suppressed DC phenotype that was not observed following thioacetamide-induced liver disease, which suggests an important role for ALD in altering the host cellular and humoral immune responses.

Chronic ethanol diet increases regulatory T‐cell activity and inhibits hepatitis C virus core‐specific cellular immune responses in mice

“…Mice vaccinated with core‐loaded DC from ethanol‐fed mice exhibited a higher CD25 + FOXP3 + and CD4+FOXP3 Treg population compared to mice immunized with DC core derived from isocaloric pair‐fed controls. These results suggest a potential interaction between chronic ethanol consumption and Treg generation, thereby suppressing DC‐mediated T‐cell sensitization against HCV core protein; further studies will be required to determine if it is due to a direct interaction of Treg with HCV core‐sensitive CD4 + and CD8 + T cells or to reduce cytokine secretion and altered antigen presentation by DC as previously described . It is also important to note that the levels of CD4 + T cells (Fig.…”

“…Tumor necrosis factor‐α and IL‐4 are cytokines have been associated with induction of a Th1 and Th2 immune response, which activate macrophages and induce B‐ and T‐cell proliferation . Expression of both of these cytokines has been proposed to play a role in both ethanol‐induced as well as HCV‐induced liver injury . We determined if the DC‐based immunization approach would also produce inhibitory effects in mice immunized with core‐loaded DC derived from ethanol or isocaloric pair‐fed (control) mice.…”

“…32,33 Expression of both of these cytokines has been proposed to play a role in both ethanol-induced as well as HCV-induced liver injury. 34,35 We determined if the DC-based immunization approach would also produce inhibitory effects in mice immunized with core-loaded DC derived from ethanol or isocaloric pair-fed (control) mice. The secretion of both of these cytokines was impaired in mice immunized with ethanol-derived and HCV core-loaded DC following stimulation of splenocytes in vitro with core protein; however, there was no difference in transforming growth factor (TGF)-b and IL-10 secretion (data not shown) ( Fig.…”

Ethanol Inhibits Antigen Presentation by Dendritic Cells

“…However, DCs derived from chronically ethanol-fed mice demonstrated reduced peptide-MHCII complex presentation compared to those from control mice, with higher expression of the inhibitory costimulatory molecule ICOS-L as well as deregulation of other costimulatory molecules, such as CD86 and B7-DC. Moreover, ethanol seems to impede cytokine release (1,5,8,15,20,21,30,34). DCs derived from chronically ethanol-fed mice exhibit normal antigen uptake (1) and degradation.…”

Immunity and inflammatory signaling in alcoholic liver disease

“…Both mDCs and pDCs are present in normal liver, but can also be recruited in response to infectious stimulation [13]. Recent studies show that chronic alcoholic liver injury is associated with inhibition of myeloid dendritic cell function [14]. However, whether alcohol affects the status of pDCs in ALD remains to be investigated.…”