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.
Highlights
Acute liver failure (ALF) is one of the most devastating syndromes observed in clinical practice
We identified that the regulation of adenosine receptors is not indispensible for GalN/LPS-induced lethality and the elevated cellular adenosine induced by adenosine 50-monophosphate (50-AMP) pretreatment could directly interfere with nuclear factor-kB (NF-kB) signaling pathway, suggesting a potential protective agent for amelioration of LPS-induced liver failure
To investigate how adenosine– adenosine receptors signal involves in the development of GalN/LPS-induced ALF, hepatic adenosine was measured at 30 min after GalN/LPS challenge
Summary
Acute liver failure (ALF) is one of the most devastating syndromes observed in clinical practice. Administration of Abbreviations: ALF, acute liver failure; GalN, D-galactosamine; LPS, lipopolysaccharide; TLR4, Toll-like receptor 4; CD14, cluster of differentiation 14; MyD88, myeloid differentiation factor-88; NF-kB, nuclear factor-kB; IL, interleukin; TNF-a, tumor necrosis factor-a; 50-AMP, adenosine 50-monophosphate; i.p., intraperitoneal; AST, aspartate transaminase; ALT, alanine transaminase; ELISA, enzyme-linked immunosorbent assay; H&E, hematoxylin and eosin; PBS, phosphate-buffered saline; ChIP, chromatin immunoprecipitation; AdoMet, S-adenosylmethionine; AdoHcy, S-adenosylhomocysteine; MCP-1, monocyte chemotactic protein-1. We identified that the regulation of adenosine receptors is not indispensible for GalN/LPS-induced lethality and the elevated cellular adenosine induced by 50-AMP pretreatment could directly interfere with NF-kB signaling pathway, suggesting a potential protective agent for amelioration of LPS-induced liver failure
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