title: Phlebotomine salivas inhibit immune inflammation-induced neutrophil migration via an autocrine DC-derived PGE2/IL-10 sequential pathway.
abstract: In the present study, we investigated whether saliva from Phlebotomus papatasi and Phlebotomus duboscqi inhibited antigen-induced neutrophil migration and the mechanisms involved in these effects. The pretreatment of immunized mice with salivary gland extracts (SGE) of both phlebotomines inhibited OVA challenge-induced neutrophil migration and release of the neutrophil chemotactic mediators, MIP-1alpha, TNF-alpha, and leukotriene B4 (LTB4). Furthermore, SGE treatment enhanced the production of anti-inflammatory mediators, IL-10 and PGE2. SGE treatments failed to inhibit neutrophil migration and MIP-1alpha and LTB4 production in IL-10-/- mice, also failing in mice treated with nonselective (indomethacin) or selective (rofecoxibe) cyclooxygenase (COX) inhibitors. COX inhibition resulted in diminished SGE-induced IL-10 production, and PGE2 release triggered by SGE remained increased in IL-10-/- mice, suggesting that prostanoids are acting through an IL-10-dependent mechanism. SGE treatments in vivo reduced the OVA-induced lymphoproliferation of spleen-derived cells. Further, the in vitro incubation of bone marrow-derived dendritic cells (DC) with SGE inhibited the proliferation of CD4+T cells from OVA-immunized mice, which was reversed by indomethacin and anti-IL-10 antibody treatments. Supporting these results, SGE induced the production of PGE2 and IL-10 by DC, which were blocked by COX inhibition. These effects were associated with the reduction of DC-membrane expression of MHC-II and CD86 by SGE treatment. Altogether, the results showed that Phlebotomine saliva inhibits immune inflammation-induced neutrophil migration by an autocrine DC sequential production of PGE2/IL-10, suggesting that the saliva 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 Sao Paulo, Av Bandeirantes, 3900, Ribeirão Preto, SP, Brazil, 14049-900.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Carregaro
authors.forename: Jesus G
authors.initials: JG
authors.lastname: Valenzuela
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
authors.forename: Renata
authors.initials: R
authors.lastname: Grespan
authors.forename: Graziela
authors.initials: G
authors.lastname: Matsumura
authors.forename: José M C
authors.initials: JM
authors.lastname: Ribeiro
authors.forename: Dia-Eldin
authors.initials: DE
authors.lastname: Elnaiem
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D019898:Autocrine Communication / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology*; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D007249:Inflammation / Q000276:immunology; D016753:Interleukin-10 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects; D010047:Ovalbumin; D010538:Peritonitis / Q000276:immunology / Q000473:pathology; D010691:Phlebotomus / Q000276:immunology*; D012463:Saliva / Q000187:drug effects / Q000276:immunology*; D014020:Tissue Extracts
chemical_list: D008070:Lipopolysaccharides; D014020:Tissue Extracts; D016753:Interleukin-10; D010047:Ovalbumin; D015232:Dinoprostone