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Modulation of innate and acquired immune responses by leukotrienes and prostaglandins


Several cells, in response to various stimuli produce arachidonic acid (AA) metabolites. AA released can either be metabolized by cyclooxygenase enzymes 1 and 2 (COX1 and COX2) ar by one of the lipoxygenases (LO), among them 5-lipoxygenase (5¬LO), originating prostaglandins (PGs) and leukotrienes, respectively. PGs induce pain, vasodilatation, increase in vascular permeability, fever, and regulate the production of cytokines and the inflammatory process. On the other hand, some cytokines are able to regulate the production of PGs, and this magnifies the importance of studies involving these mediators and cytokines, which play a role in innate and acquired immune response. Leukotrienes induce leukocyte recruitment, plasma extravasation, mucus secretion, vascular relaxation, vasoconstriction and bronchoconstriction in different inflammatory processes. Moreover, leukotrienes play an important role in modulating the synthesis and release of inflammatory cytokines, immune response, also participating in cellular activation and/or production of antibodies. These lipid mediators also modulate microorganism phagocytosis by immune system cells. In previous studies, we demonstrated that leukotrienes are involved in the systemic eosinophilia in response to infestation by Toxocara canis, but do not modulate expression of some adhesion molecules (study under preparation); recruitment of leukocytes in response to intraperitonial inoculation of Histoplasma capsulatum (Br. J. Pharmacol., 1999); and leukocyte recruitment in response to inoculation of venom from the wasp Polybia paulista (study under preparation). In order to continue our investigations on the role of leukotrienes in various inflammatory processes, we have studied the participation of these mediators in lung infection by H. capsulatum and obtained novel data, as well as extremely relevant results. We observed that inhibition of the release of leukotrienes results in death of 100% of animals infected by H. capsulatum and this phenomenon seems to be related to the intense inflammatory reaction in the lungs and the accentuated proliferation of the fungus. In this study we also demonstrated that leukotrienes regulate the release of inflammatory cytokines such as IL-1, IL-6, KC and TNFa, and some chemokines, such as MCP-1, RANTES, MIP-1 (3, MIP-2, IP-10, and MCP-1. Moreover, we demonstrated that leukotrienes are essential for the release of cytokines in the immune response, such as IL-2, IL-12, and IFNy, as well as nitric oxide (manuscripts under preparation). In order to extend the observations on the role of AA metabolites as immunoregulators, in this thematic project we aim to investigate the participation of leukotrienes and/or prostaglandins (i) in the protection induced by an exoantigen from H. capsulatum ; (ii) in infection by Strongyloides venezuelensis; (iii) in the release of cytokines and production of immunoglobulins in toxocariasis; (iv) in infection by Mycobacterium tuberculosis; (v) in oral tolerance. Due to the restoring and pharmacological effects of AA metabolites described by several authors, including ourselves, we also seek the goal of investigating the use of these metabolites as adjuvants and immunomodulators in the treatment of various infectious diseases. There are no reports so far on experiments where leukotrienes and prostaglandins have been administered in vivo with these objectives. This is due to the fact that these mediators are very unstable, in addition to being insoluble in water. In this project we also aim the development of microspheres and nanoparticles containing leukotrienes and/or prostaglandins for in vivo administration. Microspheres are polymeric particles consisting on a matricial system in which the encapsulated substance is dissolved or dispersed. These preparations present the advantages of favoring the interaction with cells in the phagocytic mononuclear system and using small amounts of the compounds. Furthermore, depending on their size, these particles can be administered through parenteral route or by inhalation, favoring its in vivo utilization. This is an innovative project, which, besides contributing for a better understanding of the immunomodulatory role of these mediators in infectious processes, may also contribute for the development of technology that will allow the use of leukotrienes and prostaglandins in the treatment of infectious and parasitic diseases. (AU)

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Scientific publications (13)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DOS SANTOS, DAIANE F.; NICOLETE, ROBERTO; DE SOUZA, PATRICIA R. M.; BITENCOURT, CLAUDIA DA S.; DOS SANTOS JUNIOR, RUBENS R.; BONATO, VANIA L. D.; SILVA, CELIO L.; FACCIOLI, LUCIA H.. Characterization and in vitro activities of cell-free antigens from Histoplasma capsulatum-loaded biodegradable microspheres. European Journal of Pharmaceutical Sciences, v. 38, n. 5, p. 548-555, . (08/01898-2, 02/12856-2)
SORGI, CARLOS ARTERIO; SECATTO, ADRIANA; FONTANARI, CAROLINE; TURATO, WALTER MIGUEL; BELANGER, CAROLINE; DE MEDEIROS, ALEXANDRA IVO; KASHIMA, SIMONE; MARLEAU, SYLVIE; COVAS, DIMAS TADEU; BOZZA, PATRICIA TORRES; et al. Histoplasma capsulatum Cell Wall beta-Glucan Induces Lipid Body Formation through CD18, TLR2, and Dectin-1 Receptors: Correlation with Leukotriene B-4 Generation and Role in HIV-1 Infection. JOURNAL OF IMMUNOLOGY, v. 182, n. 7, p. 4025-4035, . (02/12856-2)
ROCHA, R. A. S. S.; SILVA, R. A. B.; ASSED, S.; MEDEIROS, A. I.; FACCIOLI, L. H.; PECORA, J. D.; NELSON-FILHO, P.. Nitric oxide detection in cell culture exposed to LPS after Er:YAG laser irradiation. International Endodontic Journal, v. 42, n. 11, p. 992-996, . (02/12856-2)
PERES-BUZALAF, C.; DE PAULA, L.; FRANTZ, F. G.; SOARES, E. M.; MEDEIROS, A. I.; PETERS-GOLDEN, M.; SILVA, C. L.; FACCIOLI, L. H.. Control of experimental pulmonary tuberculosis depends more on immunostimulatory leukotrienes than on the absence of immunosuppressive prostaglandins. PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS, v. 85, n. 2, p. 75-81, . (02/12856-2, 00/09663-2)
PERES, CAMILA M.; PAULA, LÚCIA DE; MEDEIROS, ALEXANDRA I.; SORGI, CARLOS A.; SOARES, EDSON G.; CARLOS, DANIELA; PETERS-GOLDEN, MARC; SILVA, CÉLIO L.; FACCIOLI, LÚCIA H.. Inhibition of leukotriene biosynthesis abrogates the host control of Mycobacterium tuberculosis. Microbes and Infection, v. 9, n. 4, p. 483-489, . (00/09663-2, 02/12856-2)
BITENCOURT, CLAUDIA DA SILVA; DA SILVA, LETICIA BUENO; TARTARI PEREIRA, PRISCILLA APARECIDA; GELFUSO, GUILHERME MARTINS; FACCIOLI, LUCIA HELENA. Microspheres prepared with different co-polymers of poly(lactic-glycolic acid) (PLGA) or with chitosan cause distinct effects on macrophages. COLLOIDS AND SURFACES B-BIOINTERFACES, v. 136, p. 678-686, . (07/04741-4, 02/12856-2, 09/07169-5, 05/54855-0)
NICOLETE, ROBERTO; LIMA, KARLA DE MELO; JUNIOR, JOSE M. R.; JOSE, PETER J.; SANZ, MARIA-JESUS; FACCIOLI, LUCIA HELENA. Prostaglandin E-2-loaded microspheres as strategy to inhibit phagocytosis and modulate inflammatory mediators release. EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, v. 70, n. 3, p. 784-790, . (02/12856-2)
MACHADO, ELEUZA R.; CARLOS, DANIELA; LOURENCO, ELAINE V.; SORGI, CARLOS A.; SILVA, ERIKA V.; RAMOS, SIMONE G.; UETA, MARLENE T.; ARONOFF, DAVID M.; FACCIOLI, LUCIA H.. Counterregulation of Th2 immunity by interleukin 12 reduces host defenses against Strongyloides venezuelensis infection. Microbes and Infection, v. 11, n. 5, p. 571-578, . (02/12856-2)
MEDEIROS, ALEXANDRA I.; SA-NUNES, ANDERSON; TURATO, WALTER M.; SECATTO, ADRIANA; FRANTZ, FABIANI G.; SORGI, CARLOS A.; SEREZANI, CARLOS H.; DEEPE, JR., GEORGE S.; FACCIOLI, LUCIA H.. Leukotrienes Are Potent Adjuvant during Fungal Infection: Effects on Memory T Cells. JOURNAL OF IMMUNOLOGY, v. 181, n. 12, p. 8544-8551, . (02/12856-2)
ANIBAL, F. F.; ROGERIO, A. P.; MALHEIRO, A.; MACHADO, E. R.; MARTINS-FILHO, O. A.; ANDRADE, M. C.; SOARES, E. G.; MEDEIROS, A. I.; FACCIOLI, L. H.. Impact of MK886 on eosinophil counts and phenotypic features in toxocariasis. Scandinavian Journal of Immunology, v. 65, n. 4, p. 344-352, . (02/12856-2)
MACHADO, ELEUZA R.; UETA, MARLENE T.; LOURENÇO, ELAINE V.; ANIBAL, FERNANDA F.; SORGI, CARLOS ARTÉRIO; SOARES, EDSON G.; ROQUE-BARREIRA, MARIA C.; MEDEIROS, ALEXANDRA I.; FACCIOLI, LÚCIA H.. Leukotrienes play a role in the control of parasite burden in murine strongyloidiasis. JOURNAL OF IMMUNOLOGY, v. 175, n. 6, p. 3892-3899, . (02/12856-2)
NICOLETE‚ R.; RIUS‚ C.; PIQUERAS‚ L.; JOSE‚ P.J.; SORGI‚ C.A.; SOARES‚ E.G.; SANZ‚ M.J.; FACCIOLI‚ L.H.. Leukotriene B4-loaded microspheres: a new therapeutic strategy to modulate cell activation. BMC IMMUNOLOGY, v. 9, n. 1, p. 36, . (02/12856-2)
MACHADO, ELEUZA RODRIGUES; UETA, MARLENE TIDUKO; LOURENCO, ELAINE VICENTE; ANIBAL, FERNANDA DE FREITAS; GARCIA DA SILVA, ERICA VITALINO; ROQUE-BARREIRA, MARIA CRISTINA; COSTA-CRUZ, JULIA MARIA; FACCIOLI, LUCIA HELENA. Infectivity of Strongyloides venezuelensis is influenced by variations in temperature and time of culture. Experimental Parasitology, v. 127, n. 1, p. 72-79, . (02/12856-2)

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