title: Upregulation of Kupffer cell α2A-Adrenoceptors and downregulation of MKP-1 mediate hepatic injury in chronic alcohol exposure.
abstract: Alcohol-induced liver disease is associated with unacceptable morbidity and mortality. When activated, Kupffer cells (KCs), the resident macrophages in the liver, release proinflammatory cytokine TNF-α, a key mediator of hepatic damage. Although chronic alcohol causes increase in norepinephrine (NE) release leading to hepatic dysfunction, the mechanism of NE-induced hepatic injury in chronic alcohol exposure has not been elucidated. This study was conducted to determine whether chronic alcohol exposure increases NE and upregulates KC α(2A)-adrenoceptors (α(2A)-AR) to cause TNF-α release. We also examined the role of mitogen activated protein kinase (MAPK) phosphatase-1 (MKP-1) in this process. Male adult rats were fed the Lieber-DeCarli liquid diet containing alcohol as 36% of total calories. The animals were sacrificed after 6 weeks and blood and liver samples were harvested for further analysis. KCs from healthy male rats were cultured with alcohol for 7 days, and cells then harvested for RNA and protein analyses. Chronic alcohol exposure resulted in hepatic damage. Alcohol caused a 276% increase in circulating NE and 86% increase in TNF-α in the liver. There was a 75% and 62% decrease in MKP-1 mRNA and protein levels, respectively in the liver. In-vitro experiments revealed 121% and 98% increase in TNF-α and α(2A)-AR mRNA levels with alcohol exposure, respectively, and a 32% decrease in MKP-1 mRNA compared to controls. In summary, chronic alcohol exposure elevates NE and upregulates KC α(2A)-AR to release TNF-α. Alcohol induced downregulation of MKP-1 leads to further release of TNF-α and hepatic injury.
authors.affiliation: Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY 11030, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ajakaiye
authors.forename: Asha
authors.initials: A
authors.lastname: Jacob
authors.forename: Rongqian
authors.initials: R
authors.lastname: Wu
authors.forename: Mian
authors.initials: M
authors.lastname: Zhou
authors.forename: Youxin
authors.initials: Y
authors.lastname: Ji
authors.forename: Weifeng
authors.initials: W
authors.lastname: Dong
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Wang
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Qiang
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Chaung
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Nicastro
authors.forename: Gene F
authors.initials: GF
authors.lastname: Coppa
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D000818:Animals; D015536:Down-Regulation; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D000431:Ethanol / Q000008:administration & dosage*; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018341:Receptors, Adrenergic, alpha-2; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D009638:Norepinephrine