title: Nucleosides from Phlebotomus papatasi salivary gland ameliorate murine collagen-induced arthritis by impairing dendritic cell functions.
abstract: Among several pharmacological compounds, Phlebotomine saliva contains substances with anti-inflammatory properties. In this article, we demonstrated the therapeutic activity of salivary gland extract (SGE) of Phlebotomus papatasi in an experimental model of arthritis (collagen-induced arthritis [CIA]) and identified the constituents responsible for such activity. Daily administration of SGE, initiated at disease onset, attenuated the severity of CIA, reducing the joint lesion and proinflammatory cytokine release. In vitro incubation of dendritic cells (DCs) with SGE limited specific CD4(+) Th17 cell response. We identified adenosine (ADO) and 5'AMP as the major salivary molecules responsible for anti-inflammatory activities. Pharmacologic inhibition of ADO A2(A) receptor or enzymatic catabolism of salivary nucleosides reversed the SGE-induced immunosuppressive effect. Importantly, CD73 (ecto-5'-nucleotidase enzyme) is expressed on DC surface during stage of activation, suggesting that ADO is also generated by 5'AMP metabolism. Moreover, both nucleosides mimicked SGE-induced anti-inflammatory activity upon DC function in vitro and attenuated establishment of CIA in vivo. We reveal that ADO and 5'AMP are present in pharmacological amounts in P. papatasi saliva and act preferentially on DC function, consequently reducing Th17 subset activation and suppressing the autoimmune response. Thus, it is plausible that these constituents might be promising therapeutic molecules to target immune inflammatory diseases.
authors.affiliation: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, 14049-900 São Paulo, Brazil.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Carregaro
authors.forename: Anderson
authors.initials: A
authors.lastname: Sá-Nunes
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: Renata
authors.initials: R
authors.lastname: Grespan
authors.forename: Carlo J F
authors.initials: CJ
authors.lastname: Oliveira
authors.forename: Djalma S
authors.initials: DS
authors.lastname: Lima-Junior
authors.forename: Diego L
authors.initials: DL
authors.lastname: Costa
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
authors.forename: Cristiane M
authors.initials: CM
authors.lastname: Milanezi
authors.forename: Van My
authors.initials: VM
authors.lastname: Pham
authors.forename: David D
authors.initials: DD
authors.lastname: Brand
authors.forename: Jesus G
authors.initials: JG
authors.lastname: Valenzuela
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
authors.forename: José M C
authors.initials: JM
authors.lastname: Ribeiro
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D005260:Female; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009705:Nucleosides / Q000494:pharmacology*; D010691:Phlebotomus / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012469:Salivary Glands / Q000737:chemistry*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014020:Tissue Extracts / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D009705:Nucleosides; D014020:Tissue Extracts