Acute alcohol intoxication suppresses the interleukin 23 response to Klebsiella pneumoniae infection.
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.
Happel
Kyle I
KI
Section of Pulmonary/Critical Care Medicine, Lousiana State University Health Sciences Center, New Orleans, Louisiana, USA. khappe@lsuhsc.edu
Odden
Anthony R
AR
Zhang
Ping
P
Shellito
Judd E
JE
Bagby
Gregory J
GJ
Nelson
Steve
S
D000818:Animals; D000431:Ethanol / Q000506:poisoning*; D015870:Gene Expression / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism / Q000494:pharmacology; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000378:metabolism*; D007710:Klebsiella Infections / Q000378:metabolism*; D007711:Klebsiella pneumoniae; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology
C508841:Il23a protein, mouse; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D011994:Recombinant Proteins; D016753:Interleukin-10; D000431:Ethanol; D007371:Interferon-gamma