Acute alcohol intoxication suppresses the interleukin 23 response to Klebsiella pneumoniae infection

Abstract

Background: Bacterial pneumonia is a widely recognized infection in the alcohol-abusing patient. Interleukin 23 (IL-23) is a recently described cytokine critical for IL-17 induction and host survival during Klebsiella pneumoniae infection, a pulmonary pathogen commonly seen in alcoholics. We investigated the effect of acute alcohol intoxication on the IL-23 response to this infection.

Methods: Male C57BL/6 mice were given an intraperitoneal injection of ethanol (3.0 g/kg) or phosphate-buffered saline (PBS) 30 minutes before infection. Alveolar macrophages (AM) were cultured with bacteria in ethanol (0, 50, and 100 mM) to determine alcohol's effect on AM IL-23 expression, the bioactivity of which was determined by splenocyte IL-17 inducing activity. The role of IL-10 in alcohol-mediated suppression of AM IL-23 p19 mRNA expression was assessed using wild-type (WT) and IL-10 knock-out (KO) mice. Efficacy of AM pretreatment with interferon gamma (IFN-gamma) on IL-23 expression before ethanol exposure and infection was evaluated.

Results: In vivo, acute intoxication suppresses the lung and bronchoalveolar lavage cell IL-23 response to pathogen. This effect was confirmed in vitro as ethanol dose-dependently inhibits AM IL-23 during infection. Acute intoxication increases lung and BAL cell IL-10 mRNA expression 2 hours after in vivo infection and, in vitro, recombinant IL-10 inhibits AM IL-23 expression. However, alcohol impairs IL-23 similarly in AM harvested from both WT and IL-10 KO mice. Interferon gamma pretreatment strongly inhibits AM IL-23 production in both the presence and absence of alcohol.

Conclusions: Acute alcohol intoxication inhibits the pulmonary IL-23 response to K. pneumoniae infection both in vivo and in vitro, an effect independent of IL-10 induction. Interferon gamma priming antagonizes IL-23 and is, therefore, not likely to be a useful adjuvant therapy in restoring IL-23/IL-17 responses during infection and intoxication.