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Prostaglandin E₂ Is a Major Inhibitor of Dendritic Cell Maturation and Function in Ixodes scapularis Saliva¹

Anderson Sá-Nunes^*, André Bafica^,, David A. Lucas^2,, Thomas P. Conrads^3,, Timothy D. Veenstra, John F. Andersen^*, Thomas N. Mather^¶, José M. C. Ribeiro^* and Ivo M. B. Francischetti^4,*

^* Section of Vector Biology, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases/National Institutes of Health, Rockville, MD 20852; Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases/National Institutes of Health, Bethesda, MD 20892; Division of Immunology, Microbiology and Parasitology Department, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil; Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, National Cancer Institute/National Institutes of Health, Frederick, MD 21702; and ^¶ Center for Vector-Borne Disease, University of Rhode Island, Kingston, RI 02881

Tick saliva is thought to contain a number of molecules that prevent host immune and inflammatory responses. In this study, the effects of Ixodes scapularis saliva on cytokine production by bone marrow-derived dendritic cells (DCs) from C57BL/6 mice stimulated by TLR-2, TLR-4, and TLR-9 ligands were studied. Saliva at remarkably diluted concentrations (<1/2000) promotes a dose-dependent inhibition of IL-12 and TNF- production induced by all TLR ligands used. Using a combination of fractionation techniques (microcon filtration, molecular sieving, and reversed-phase chromatography), we unambiguously identified PGE₂ as the salivary inhibitor of IL-12 and TNF- production by DCs. Moreover, we have found that I. scapularis saliva (dilution 1/200; 10 nM PGE₂) marginally inhibited LPS-induced CD40, but not CD80, CD86, or MHC class II expression. In addition, saliva significantly suppressed the ability of DCs to stimulate Ag-specific CD4⁺ T cell proliferation and IL-2 production. Notably, the effect of saliva on DC maturation and function was reproduced by comparable concentrations of standard PGE₂. These findings indicate that PGE₂ accounts for most inhibition of DC function observed with saliva in vitro. The role of salivary PGE₂ in vector-host interaction and host immune modulation and inflammation in vivo is also discussed. This study is the first to identify molecularly a DC inhibitor from blood-sucking arthropods.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funding from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and from National Institutes of Health Grant R01 AI37230 (to T.N.M.). It is contribution number 5078 of the Rhode Island Agricultural Experiment Station (to T.N.M.). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract NO1-CO-12400 (to T.D.V.).

² Current address: Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213-1863.

³ Current address: University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213-1863.

⁴ Address correspondence and reprint requests to Dr. Ivo M. B. Francischetti, Section of Vector Biology, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases/National Institutes of Health, Rockville, MD 20852. E-mail address: ifrancischetti{at}niaid.nih.gov

⁵ Abbreviations used in this paper: DC, dendritic cell; LTQ-FTICR, linear ion trap-Fourier transform ion cyclotron resonance mass spectrometer; MS, mass spectrometry; PGN, peptidoglycan; RPLC, reversed-phase liquid chromatography.

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