Additive Inhibition of Dendritic Cell Allostimulatory Capacity by Alcohol and Hepatitis C Is Not Restored by DC Maturation and Involves Abnormal IL-10 and IL-2 Induction

Authors


  • This work was supported by PHS grants AA12862 and AA008577 from the National Institute of Alcohol Abuse and Alcoholism, and its contents are the responsibility of the authors and do not necessarily represent the official views of the NIAAA.

Gyongyi Szabo, MD, PhD, Professor, Department of Medicine, University of Massachusetts Medical School, LRB 215, 364 Plantation Street, Worcester, MA 01605-2324; Fax: 508-856-4770; E-mail: gyongyi.szabo@umassmed.edu

Abstract

Background: Excessive alcohol use results in impaired immunity, and it is associated with increased incidence and progression of chronic hepatitis C virus (HCV) infection. Here we investigated the effects of HCV infection and alcohol on myeloid dendritic cells (DC) that are critical in antiviral immunity.

Methods: Immature and mature DCs were generated from monocytes of chronic HCV infected patients (HCV-DC) and controls (N-DC) with IL-4 plus granulocyte-macrophage colony stimulating factor (GM-CSF) in the presence or absence of alcohol (25 mM). DC allostimulatory capacity was tested in mixed lymphocyte reaction (MLR) and cytokine production by ELISA.

Results: Allostimulatory capacity of HCV-DCs was reduced compared to N-DCs and it was further inhibited by alcohol treatment (p < 0.01). MLR was also decreased with alcohol-treated N-DCs. DC phenotypic markers and apoptosis were comparable between HCV-DCs and N-DCs irrespective of alcohol treatment. However, HCV-DCs and alcohol-treated N-DCs exhibited elevated IL-10 and reduced IL-12 production. Reduced MLR with HCV-DCs and its further inhibition by alcohol coexisted with decreasing IL-2 levels (p < 0.017). DC maturation partially improved but failed to fully restore the reduced allostimulatory function of either alcohol-treated or alcohol-naïve HCV-DCs (p < 0.018).

Conclusions: Alcohol and HCV independently and together inhibit DC allostimulatory capacity, increase IL-10, reduce IL-12 and IL-2 production that cannot be normalized by DC maturation. HCV and alcohol interact to modulate innate and adaptive immune responses via dendritic cells.

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