title: Adenosine 5'-monophosphate ameliorates D-galactosamine/lipopolysaccharide-induced liver injury through an adenosine receptor-independent mechanism in mice.
abstract: D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced lethality and acute liver failure is dependent on endogenously produced inflammatory cytokines. Adenosine has been proven to be a central role in the regulation of inflammatory response. It is not entirely clear that which adenosine action is actually crucial to limiting inflammatory tissue destruction. Here we showed that GalN/LPS challenge elevated hepatic adenosine and induced lethality in adenosine receptor-deficient mice with equal efficiency as wild-type mice. In GalN/LPS-treated mice, pretreatment with adenosine 5'-monophosphate (5'-AMP) significantly elevated hepatic adenosine level and reduced mortality through decreasing cytokine and chemokine production. In RAW264.7 cells, 5'-AMP treatment inhibited the production of inflammatory cytokines, which is not mediated through adenosine receptors. 5'-AMP failed to attenuate LPS-induced nuclear factor-κB (NF-κB) p65 nuclear translocation, but reduced LPS-induced recruitment of NF-κB p65 to inflammatory gene promoters and decreased LPS-induced enrichment of H3K4 dimethylation at the tumor necrosis factor-α (TNF-α) promoter, which was involved in 5'-AMP-induced elevation of cellular adenosine and a decline of methylation potential. In vitro biochemical analysis revealed that adenosine directly attenuated recruitment of NF-κB to the TNF-α and interleukin-6 promoters. Our findings demonstrate that 5'-AMP-inhibiting inflammatory response is not mediated by adenosine receptors and it may represent a potential protective agent for amelioration of LPS-induced liver injury.
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing 210094, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: East Hospital, Tongji University, Shanghai 200120, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing 210094, China.
authors.forename: P
authors.initials: P
authors.lastname: Yang
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing 210094, China.
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing 210094, China.
authors.forename: L
authors.initials: L
authors.lastname: Xia
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing 210094, China.
authors.forename: M
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing 210094, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing 210094, China.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: The State Kay Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Hua
authors.affiliation: 1] Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing 210094, China [2] The State Kay Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000249:Adenosine Monophosphate / Q000008:administration & dosage* / Q000378:metabolism*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005688:Galactosamine / Q000009:adverse effects*; D006801:Humans; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008099:Liver / Q000293:injuries / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D018047:Receptors, Purinergic P1; D014409:Tumor Necrosis Factor-alpha; D000249:Adenosine Monophosphate; D005688:Galactosamine