Ethanol alters cellular activation and CD14 partitioning in lipid rafts.
Alcohol consumption interferes with innate immunity. In vivo EtOH administration suppresses cytokine responses induced through Toll-like receptor 4 (TLR4) and inhibits TLR4 signaling. Actually, EtOH exhibits a generalized suppressive effect on signaling and cytokine responses induced by through most TLRs. However, the underlying mechanism remains unknown. RAW264.7 cells were treated with LPS or co-treated with EtOH or with lipid raft-disrupting drugs. TNF-alpha production, IRAK-1 activation, and CD14 partition were evaluated. EtOH or nystatin, a lipid raft-disrupting drug, suppressed LPS-induced production of TNF-alpha. The suppressive effect of EtOH on LPS-induced TNF-alpha production was additive with that of methyl-beta-cyclodextrin (MCD), another lipid raft-disrupting drug. EtOH interfered with IRAK-1 activation, an early TLR4 intracellular signaling event. Cell fractionation analyses show that acute EtOH altered LPS-related partition of CD14, a critical component of the LPS receptor complex. These results suggest a novel mechanism of EtOH action that involves interference with lipid raft clustering induced by LPS. This membrane action of EtOH might be one of the mechanisms by which EtOH acts as a generalized suppressor for TLR signaling.
Dai
Qun
Q
Department of Cellular Biology and Anatomy, Louisiana State University Health Science Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
Zhang
Jun
J
Pruett
Stephen B
SB
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D047392:beta-Cyclodextrins / Q000008:administration & dosage
D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D047392:beta-Cyclodextrins; D000431:Ethanol; C031215:betadex