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 γ (IFN‐γ) 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 γ 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 γ 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.