Effect of alcohol consumption on host release of interleukin-17 during pulmonary infection with Klebsiella pneumoniae.
BACKGROUND
A link between alcohol abuse and bacterial pneumonia has been recognized for centuries, but mechanisms to explain this relationship are unclarified. Interleukin-17 (IL-17) is a lymphocyte-derived cytokine that is part of the inflammatory cytokine cascade. Previous studies from our laboratory indicated that IL-17 is released in lung tissue in a murine model of bacterial pneumonia caused by Klebsiella pneumoniae. The effects of alcohol consumption on pulmonary release of IL-17 are unknown.


METHODS
Mice were maintained on 20% ethanol in drinking water or on a control diet without alcohol. After 2 weeks, alcohol and control mice were challenged with intratracheal K. pneumoniae. Mice were followed for survival after bacterial challenge, neutrophil recruitment was assayed as myeloperoxidase, and IL-17 was measured in lung lavage fluid by enzyme-linked immunosorbent assay. In additional experiments, splenocytes from control mice were incubated with ethanol in vitro, and release of IL-17 was measured in culture supernatants. Finally, control and alcohol mice received intrapulmonary gene transfer of E-1-deleted adenovirus containing the murine IL-17 gene. These mice were then challenged with K. pneumoniae and followed for survival and neutrophil recruitment.


RESULTS
In these studies, we demonstrate that a 2-week history of ethanol consumption in mice suppresses release of IL-17 into lung tissue, decreases neutrophil recruitment, and increases mortality from experimental K. pneumonia. In vitro experiments confirm a direct suppressive effect of ethanol on the release of IL-17 from splenocytes. In vivo administration of the IL-17 gene in an adenoviral vector to alcohol-consuming mice results in release of IL-17 into lavage fluid and normalizes neutrophil recruitment and mortality after bacterial challenge.


CONCLUSIONS
The results of these experiments strongly implicate IL-17 as an important pathway for the immunosuppression associated with alcohol abuse and support gene therapeutic approaches to augment immune function in the alcoholic host or to treat infections associated with alcoholism.
Shellito
J E
JE
Department of Medicine, Louisiana State University Health Sciences Center Alcohol Research Center, New Orleans, Louisiana 70112, USA. jshell@lsuhsc.edu
quan Zheng
M
M
Ye
P
P
Ruan
S
S
Shean
M K
MK
Kolls
J
J
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured; D004326:Drinking; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D022761:Gene Transfer, Horizontal; D015316:Genetic Therapy; D020381:Interleukin-17 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D007710:Klebsiella Infections / Q000503:physiopathology*; D007711:Klebsiella pneumoniae; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology; D009195:Peroxidase / Q000032:analysis; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000401:mortality; D012333:RNA, Messenger / Q000032:analysis; D013154:Spleen / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism
D020381:Interleukin-17; D012333:RNA, Messenger; D000431:Ethanol; D009195:Peroxidase