Alcohol
Volume 27, Issue 1 , Pages 37-41, May 2002

Lymphocyte-mediated liver injury in alcohol-related hepatitis☆

  • Robert G. Batey

      Affiliations

    • Corresponding Author InformationCorresponding author. Department of Gastroenterology, John Hunter Hospital, Locked Bag 1, Hunter Regional Mail Centre, Newcastle, 2310, NSW, Australia. Tel.: +61-2-4921-3486; fax: +61-2-4921-3998.(R.G. Batey)
    • ,
  • Qi. Cao
    • ,
  • Belinda Gould

Department of Gastroenterology, John Hunter Hospital, New Lambton Heights, Newcastle 2305, NSW, Australia

Received 23 November 2001; received in revised form 11 February 2002; accepted 11 February 2002.

Abstract 

The pathogenesis of alcohol-related liver disease (ALD) remains inadequately explained. Increasing alcohol intake is associated with an increased risk of ALD, but many heavy drinkers develop no liver damage. An explanation for ALD susceptibility requires theories that extend beyond a biochemical understanding of alcohol metabolism. Several hepatic cell populations are involved in the pathogenesis of liver injury. The liver-associated lymphocyte (LAL) response to alcohol intake plus immune stimulation may determine susceptibility to liver damage. We have isolated rat LALs and demonstrated the following: (1) Liver-associated lymphocytes differ from the peripheral blood lymphocyte pool; the CD8:CD4 ratio is higher in the LAL population than in peripheral blood. (2) Tumor necrosis factor-alpha (TNF-α) and interleukin-6 production by these cells is suppressed by regular alcohol intake. (3) Tumor necrosis factor-α and interleukin-6 production by LALs is increased after parenteral administration of concanavalin A (Con A) and by Con A in in vitro LAL cultures obtained from healthy (control) and ethanol-consuming rats. (4) In vivo stimuli that lead to increased cytokine production by LALs lead, within 12–24 h, to increased hepatocyte necrosis [elevated alanine aminotransferase (ALT) levels] and apoptosis. (5) Liver-associated lymphocytes isolated from ethanol-consuming rats, transferred to non-ethanol-consuming rats, confer on the latter animals an ethanol-consuming response to Con A. (6) Cytokine release by LALs is quantitatively as significant as that from Kupffer cells after exposure to lipopolysaccharide. (7) In co-culture studies inhibition of TNF-α activity reduces hepatocyte apoptosis induced in the presence of activated LALs. (8) Finally, nuclear factor-kappa B inhibition decreases production of nitric oxide and TNF-α, with an associated reduction in hepatocyte apoptosis. In summary, our study findings support the suggestion that a role for LALs exists in the pathogenesis of alcohol and Con A–mediated liver disease.

Keywords:  Alcohol-related liver disease, Cytokines, Liver-associated lymphocytes

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☆ Editor: T.R. Jerrells

PII: S0741-8329(02)00213-6

Alcohol
Volume 27, Issue 1 , Pages 37-41, May 2002

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