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Ethanol and the ubiquitin‐proteasome pathway of alveolar macrophages

The ubiquitin‐proteasome pathway is critical in the inflammatory host response to bacterial infections. Alcohol exposure predisposes to infection, particularly pneumonia caused by Klebsiella pneumoniae (Kp). We tested the effect of alcohol on the ubiquitin‐proteasome pathway using exposure to Klebsiella pneumoniae as our model. Murine alveolar macrophage cell line (MH‐S), macrophage/monocyte cell line (RAW264.7) or primary alveolar macrophages from Balb/c mice were exposed to different alcohol concentrations and challenged with 2x106 colony forming units of heat‐killed Klebsiella. At various time points cell lysates were analyzed for 20S proteasome activity by measuring the release of proteasome‐cleaved fluorigenic substrate. We observed that 20S proteasome activity was decreased, in a dose‐dependent manner, by as much as 61% in the groups exposed to ethanol, as compared to the control group (p<0.05). Cell lysates were also assayed, by Western analysis, for levels of total intracellular free protein ubiquitin and of polyubiquitinated proteins. We observed that alcohol alters levels of intracellular polyubiquitinated proteins but does not affect levels of intracellular free ubiquitin. We conclude that pulmonary infection caused by Klebsiella may be enhanced by alcohol exposure through inhibition of the ubiquitin‐proteasome pathway of alveolar macrophages.