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Published online before print April 7, 2008

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(Journal of Leukocyte Biology. 2008;84:104-114.)
© 2008 by Society for Leukocyte Biology

Phlebotomine salivas inhibit immune inflammation-induced neutrophil migration via an autocrine DC-derived PGE₂/IL-10 sequential pathway

Vanessa Carregaro^*, Jesus G. Valenzuela, Thiago M. Cunha, Waldiceu A. Verri, Jr., Renata Grespan, Graziela Matsumura, José M. C. Ribeiro, Dia-Eldin Elnaiem, João S. Silva^* and Fernando Q. Cunha^,1

^* Department of Biochemistry and Immunology and
Pharmacology, School of Medicine of Ribeirão Preto, University of Sao Paulo, Sao Paulo, Brazil; and
Vector Molecular Biology Unit and
Vector Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

¹Correspondence: Department of Pharmacology, School of Medicine of Ribeirão Preto, University of Sao Paulo, Av Bandeirantes, 3900, Ribeirão Preto, SP, Brazil, 14049-900. E-mail: fdqcunha{at}fmrp.usp.br

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-1, TNF-, 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-1 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.

Key Words: antigen presentation • anti-inflammatory mediators • inflammatory diseases • cytokines • insect saliva • sand fly