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Lutzomyia longipalpis Salivary Peptide Maxadilan Alters Murine Dendritic Cell Expression of CD80/86, CCR7, and Cytokine Secretion and Reprograms Dendritic Cell-Mediated Cytokine Release from Cultures Containing Allogeneic T Cells¹

Department of Microbiology Immunology and Pathology, Colorado State University, Fort Collins, CO 80523

Leishmania protozoan parasites, the etiologic agent of leishmaniasis, are transmitted exclusively by phlebotomine sand flies of the genera Phlebotomus and Lutzomyia. In addition to parasites, the infectious bite inoculum contains arthropod salivary components. One well-characterized salivary component from Lutzomyia longipalpis is maxadilan (MAX), a vasodilator acting via the type I receptor for the pituitary cyclic AMP activating peptide. MAX has been shown to elicit immunomodulatory effects potentially dictating immune responses to Leishmania parasites. When exposed to MAX, both resting and LPS-stimulated dendritic cells (DCs) show reduced CD80 and CD86 expression on most DCs in vitro. However, CD86 expression is increased significantly on a subpopulation of DCs. Furthermore, MAX treatment promoted secretion of type 2 cytokines (IL-6 and IL-10) while reducing production of type 1 cytokines (IL-12p40, TNF-, and IFN-) by LPS-stimulated DCs. A similar trend was observed in cultures of MAX-treated DCs containing naive allogeneic CD4⁺ T cells: type 2 cytokines (IL-6 and IL-13) increased while type 1 cytokines (TNF- and IFN-) decreased. Additionally, the proinflammatory cytokine IL-1β was increased in cultures containing MAX-treated mature DCs. MAX treatment of LPS-stimulated DCs also prevented optimal surface expression of CCR7 in vitro. These MAX-dependent effects were evident in DCs from both Leishmania major-susceptible (BALB/c) and -resistant (C3H/HeN) murine strains. These data suggest that modification of DC phenotype and function by MAX likely affects crucial cellular components that determine the pathological response to infection with Leishmania.

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 National Institutes of Health Grant R01 AI65784 to R.G.T.

² W.H.W. and K.E.P. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. William H. Wheat and Dr. Kristen E. Pauken, Department of Microbiology Immunology and Pathology, College of Veterinary Medicine and Biological Sciences, Colorado State University, 1619 Campus Delivery, Fort Collins, CO 80523. E-mail addresses: wheatw{at}colostate.edu and kristen.pauken{at}colostate.edu

⁴ Abbreviations used in this paper: Lm, Leishmania major; BM-DC, bone marrow-derived dendritic cell; DC, dendritic cell; MAX, maxadilan; MFI, mean fluorescence intensity; PACAP, pituitary adenylate cyclase-activating peptide; rm, recombinant murine; VIP, vasoactive intestinal peptide.