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Leukotrienes Are Potent Adjuvant during Fungal Infection: Effects on Memory T Cells¹

Alexandra I. Medeiros^*, Anderson Sá-Nunes^*, Walter M. Turato^*, Adriana Secatto^*, Fabiani G. Frantz^*, Carlos A. Sorgi^*, Carlos H. Serezani, George S. Deepe, Jr. and Lúcia H. Faccioli^2,*

^* Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; and Division of Infectious Diseases, Veterans Affairs Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45267

Leukotrienes (LTs) are potent lipid mediators involved in the control of host defense. LTB₄ induces leukocyte accumulation, enhances phagocytosis and bacterial clearance, and increases NO synthesis. LTB₄ is also important in early effector T cell recruitment that is mediated by LTB₄ receptor 1, the high-affinity receptor for LTB₄. The aims of this study were to evaluate whether LTs are involved in the secondary immune response to vaccination in a murine model of Histoplasma capsulatum infection. Our results demonstrate that protection of wild-type mice immunized with cell-free Ags from H. capsulatum against histoplasmosis was associated with increased LTB₄ and IFN- production as well as recruitment of memory T cells into the lungs. In contrast, cell-free Ag-immunized mice lacking 5-lipoxygenase^–/–, a critical enzyme involved in LT synthesis, displayed a marked decrease on recruitment of memory T cells to the lungs associated with increased synthesis of TGF-β as well as IL-10. Strikingly, these effects were associated with increased mortality to 5-lipoxygenase^–/–-infected mice. These data establish an important immunomodulatory role of LTs, in both the primary and secondary immune responses to histoplasmosis.

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 grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo (02/07849-7; 02/12856-2), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), from Brazil and American Lung Association.

² Address correspondence and reprint requests to Dr. Lúcia H. Faccioli, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café s/n^o, Ribeirão Preto, São Paulo 14040-903, Brazil. E-mail address: faccioli{at}fcfrp.usp.br

³ Abbreviations used in this paper: LT, leukotriene; 5-LO, 5-lipoxygenase; AA, arachidonic acid; BHI, brain-heart infusion; BLT1, LTB₄ receptor 1; CFAg, cell-free Ag; DTH, delayed-type hypersensitivity; FLAP, 5-LO-activating protein; Hsp, heat shock protein; i.t., intratracheal; KC, keratinocyte-derived chemokine; neg, negative; p.o., perorally; WT, wild type.