title: Different effects of acute and chronic ethanol on LPS-induced cytokine production and TLR4 receptor behavior in mouse peritoneal macrophages.
abstract: Both binge and chronic heavy drinking can adversely affect the immune system, but the effects seem to be at least partly dependent on the manner of ethanol (EtOH) consumption. Previous study results from several labs have clearly demonstrated that acute administration of EtOH interferes with innate immune responses. Specifically, EtOH has a general inhibitory effect on cytokine and chemokine production induced by various Toll-like receptor (TLR) ligands, and it suppresses signaling on several levels along the TLR signaling pathways. However, it is not clear whether chronic exposure to ethanol has the same effects or not. The purpose of this study was to investigate the difference between the effect of chronic versus acute EtOH exposure on LPS-induced cytokine production and clustering of components of the TLR4 complex, which is an important early signaling event. Some groups of mice received acute EtOH by oral gavage using our binge drinking model and/or chronic administration of EtOH at 20% (w/v) in the drinking water as the sole liquid source for 4 wk. The cellular distribution of CD14 and TLR4 were studied by confocal microscopy following exposure of peritoneal cells to LPS locally in vivo, and cytokine production in peritoneal fluid and serum was measured by ELISA after LPS injection via a tail vein. Chronic EtOH exposure did not consistently cause significant changes in LPS-induced cytokine production. However, mice previously exposed to chronic EtOH treatment became partially resistant to the suppressive effects of acute EtOH administration with regard to cytokine production. As we have reported previously, acute EtOH treatment suppressed the LPS-induced clustering of TLR4 and CD14 in peritoneal macrophages. However, peritoneal cells from mice treated with chronic EtOH exhibited a greater amount of intracellular expression of CD14 instead of CD14/TLR4 clustering on the membrane following LPS exposure. The results demonstrate different effects of chronic versus acute EtOH treatment on LPS-induced cytokine production in mice. Partial tolerance to the effect of acute EtOH administration caused by chronic EtOH treatment suggests a compensatory mechanism is induced by chronic EtOH administration. Acute EtOH exposure acts probably by disrupting the receptor clustering following LPS recognition, whereas adaptations induced by chronic EtOH treatment seem to involve alteration of LPS receptor expression.
authors.affiliation: Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Dai
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Pruett