Acute ethanol administration profoundly alters poly I:C-induced cytokine expression in mice by a mechanism that is not dependent on corticosterone.
Polyinosinic polycytidylic acid (poly I:C) is an analog of double stranded RNA, which is a common replication intermediate for many viruses. It acts through a toll-like receptor (TLR3) to induce a group of cytokines that can mediate host resistance to viruses and some cancers. The effect of ethanol (EtOH) on induction of this set of cytokines has not been determined. Mice were treated with a single dose of EtOH (by gavage) at the same time as poly I:C was administered (intraperitoneally), and cytokine mRNA expression was measured by RNAse protection assay. Concentrations of IFN-alpha, IL-10, and IL-12 in the serum were measured by ELISA. A single dose of EtOH suppressed induction of mRNA for IFN-alpha, IFN-beta, IFN-gamma, IL-6, IL-9, IL-12, and IL-15. The concentrations of IFN-alpha and IL-12 in the serum were also decreased. In contrast, IL-10 was minimally induced by poly I:C alone, but it was substantially induced by poly I:C plus EtOH. Dose response and time course studies demonstrated that significant alterations of IFN-alpha, IL-10, and IL-12 expression occurred at dosages as low as 4 g/kg (a dosage previously shown to produce blood EtOH concentrations of approximately 0.2%) and that alterations persisted at least 4-6 hr after administration of EtOH. The glucocorticoid synthesis inhibitor, aminoglutethimide, diminished corticosterone levels to normal, but did not block the effects of EtOH on cytokine expression. These results demonstrate that EtOH affects the expression of poly I:C-induced cytokines and that this action is not mediated by corticosterone. These results plus previously published findings are consistent with the idea that EtOH may be a generalized suppressor of toll-like receptor signaling.
Pruett
Stephen B
SB
Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, 1501 Kings Hwy., Shreveport, LA 71130, USA. spruet@LSUHSC.edu
Fan
Ruping
R
Zheng
Qiang
Q
D000284:Administration, Oral; D000616:Aminoglutethimide / Q000494:pharmacology; D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D003345:Corticosterone / Q000502:physiology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D007274:Injections, Intraperitoneal; D007369:Interferon Inducers / Q000008:administration & dosage / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors
D002492:Central Nervous System Depressants; D016207:Cytokines; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D007369:Interferon Inducers; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D000616:Aminoglutethimide; D000431:Ethanol; D011070:Poly I-C; D003345:Corticosterone