Cold-inducible RNA-binding protein is an important mediator of alcohol-induced brain inflammation.
Binge drinking has been associated with cerebral dysfunction. Ethanol induced microglial activation initiates an inflammatory process that causes upregulation of proinflammatory cytokines which in turn creates neuronal inflammation and damage. However, the molecular mechanism is not fully understood. We postulate that cold-inducible RNA-binding protein (CIRP), a novel proinflammatory molecule, can contribute to alcohol-induced neuroinflammation. To test this theory male wild-type (WT) mice were exposed to alcohol at concentrations consistent to binge drinking and blood and brain tissues were collected. At 5 h after alcohol, a significant increase of 53% in the brain of CIRP mRNA was observed and its expression remained elevated at 10 h and 15 h. Brain CIRP protein levels were increased by 184% at 10 h and remained high at 15 h. We then exposed male WT and CIRP knockout (CIRP(-/-)) mice to alcohol, and blood and brain tissues were collected at 15 h post-alcohol infusion. Serum levels of tissue injury markers (AST, ALT and LDH) were significantly elevated in alcohol-exposed WT mice while they were less increased in the CIRP(-/-) mice. Brain TNF-α mRNA and protein expressions along with IL-1β protein levels were significantly increased in WT mice, which was not seen in the CIRP(-/-) mice. In cultured BV2 cells (mouse microglia), ethanol at 100 mM showed an increase of CIRP mRNA by 274% and 408% at 24 h and 48 h respectively. Corresponding increases in TNF-α and IL-1β were also observed. CIRP protein levels were markedly increased in the medium, suggesting that CIRP was secreted by the BV2 cells. From this we conclude that alcohol exposure activates microglia to produce and secrete CIRP and possibly induce pro-inflammatory response and thereby causing neuroinflammation. CIRP could be a novel mediator of alcohol-induced brain inflammation.
Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York, United States of America.
Salil R
SR
Rajayer
Asha
A
Jacob
Weng-Lang
WL
Yang
Mian
M
Zhou
Wayne
W
Chaung
Ping
P
Wang
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D004660:Encephalitis / Q000139:chemically induced* / Q000378:metabolism*; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D015415:Biomarkers; C106176:Cirbp protein, mouse; D053583:Interleukin-1beta; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol