title: Caffeine inhibits the activation of hepatic stellate cells induced by acetaldehyde via adenosine A2A receptor mediated by the cAMP/PKA/SRC/ERK1/2/P38 MAPK signal pathway.
abstract: Hepatic stellate cell (HSC) activation is an essential event during alcoholic liver fibrosis. Evidence suggests that adenosine aggravates liver fibrosis via the adenosine A2A receptor (A2AR). Caffeine, which is being widely consumed during daily life, inhibits the action of adenosine. In this study, we attempted to validate the hypothesis that caffeine influences acetaldehyde-induced HSC activation by acting on A2AR. Acetaldehyde at 50, 100, 200, and 400 μM significantly increased HSC-T6 cells proliferation, and cell proliferation reached a maximum at 48 h after exposure to 200 μM acetaldehyde. Caffeine and the A2AR antagonist ZM241385 decreased the cell viability and inhibited the expression of procollagen type I and type III in acetaldehyde-induced HSC-T6 cells. In addition, the inhibitory effect of caffeine on the expression of procollagen type I was regulated by A2AR-mediated signal pathway involving cAMP, PKA, SRC, and ERK1/2. Interestingly, caffeine's inhibitory effect on the expression of procollagen type III may depend upon the A2AR-mediated P38 MAPK-dependent pathway.
  
  
  CONCLUSIONS
  Caffeine significantly inhibited acetaldehyde-induced HSC-T6 cells activation by distinct A2AR mediated signal pathway via inhibition of cAMP-PKA-SRC-ERK1/2 for procollagen type I and via P38 MAPK for procollagen type III.
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Institute for Liver Disease of Anhui Medical University, Hefei, Anhui, China.
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.affiliation: The 105th Hospital of PLA, Hefei, Anhui, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Guan
authors.affiliation: The First Hospital of Anqing, Anqing, Anhui, China.
authors.forename: Wanzhi
authors.initials: W
authors.lastname: Yang
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Institute for Liver Disease of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Institute for Liver Disease of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Han
authors.initials: H
authors.lastname: Zhao
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Institute for Liver Disease of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Institute for Liver Disease of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Lv
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Institute for Liver Disease of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000079:Acetaldehyde / Q000494:pharmacology*; D002110:Caffeine / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016391:Genes, src / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D043705:Receptor, Adenosine A2A; D002110:Caffeine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000079:Acetaldehyde