title: Inhibition of the hyaluronan oligosaccharides inflammatory response: reduction of adenosine 2A receptor activation by EPAC and PKA.
abstract: The aim of this study was to investigate the involvement of exchange proteins directly activated by cyclic adenosine (ADO) monophosphate (EPAC) in 4-mer hyaluronan (HA) oligosaccharide-induced inflammatory response in mouse normal synovial fibroblasts (NSF). Treatment of NSF with 4-mer HA increased Toll-like receptor-4, TNF-alpha and IL-1beta mRNA expression and of the related proteins, as well as nuclear factor kappaB (NF-kB) activation. Addition to NSF, previously stimulated with 4-mer HA oligosaccharides, of ADO significantly reduced NF-kB activation, TNF-alpha and IL-1beta expression. The pre-treatment of NSF with cyclic ADO monophosphate and/or PKA and/or EPAC-specific inhibitors significantly inhibited the anti-inflammatory effect exerted by ADO. In particular, the EPAC inhibitor reduced the ADO effect to a major extent than the PKA inhibitor. These results mean that both PKA and EPAC pathways are involved in ADO-induced NF-kB inhibition although EPAC seems to be more involved than PKA.
authors.affiliation: Department of Biomedical Sciences and Morphological and Functional Images, Section of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, Italy.
authors.forename: Giuseppe M
authors.initials: GM
authors.lastname: Campo
authors.forename: Angela
authors.initials: A
authors.lastname: Avenoso
authors.forename: Angela
authors.initials: A
authors.lastname: D'Ascola
authors.forename: Michele
authors.initials: M
authors.lastname: Scuruchi
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Nastasi
authors.forename: Alberto
authors.initials: A
authors.lastname: Calatroni
authors.forename: Salvatore
authors.initials: S
authors.lastname: Campo
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000494:pharmacology*; D007249:Inflammation / Q000473:pathology; D008297:Male; D008811:Mice, Inbred DBA; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009844:Oligosaccharides / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A / Q000187:drug effects* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D020662:Guanine Nucleotide Exchange Factors; D052002:NF-kappa B p50 Subunit; D009844:Oligosaccharides; C116122:RAPGEF3 protein, human; D043705:Receptor, Adenosine A2A; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C073701:Nfkb1 protein, mouse; D006820:Hyaluronic Acid; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: EPAC; TLRs; adenosine; cytokines; hyaluronan; inflammation; synoviocytes