MODULATION OF IMMUNE RESPONSE BY LEUKOTRIENES

FACCIOLI L. H.(1)

(1)Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo

Leukotrienes are best known as bronchoconstrictor and vasoactive mediators released by mast cells that contribute to asthmatic responses (1). They are produced by all myeloid cell lineages in response to a different stimuli and their broader participation in a wide array of pathologic inflammatory and acquired immune responses is increasingly recognized (2, 3, 4, 5). Much less well appreciated is their role in innate immune responses. Leukotrienes can be generated in response to microbial stimuli and it mediate a variety of antimicrobial functions. Moreover, a variety of conditions associated with increased susceptibility to infection are characterized by a relative deficiency of leukotrienes production. Leukotrienes biosynthesis involves the release of AA from membrane phospholipids by Ca2+–dependent cytosolic phospholipase A2 (cPLA2) and it´s conversion, by 5-lypoxigenase enzyme (5-LO), into leukotriene A4 (LTA4),  LTA4 is then enzymatically converted to LTB4 by LTA4–hydrolase  or to leukotriene C4 (LTC4) by addition of a molecule of glutathione through the action of LTC4–synthase (6, 7). We have been investigating the effects of leukotriene synthesis inhibition during the immune response in a murine model of histoplasmosis, tuberculosis and strongyloidiasis. Moreover, using 5-LO KO mice, we investigated the effects of abscence of leukotriene deficiency during the infection. The results reveal that leukotrienes play an intrinsic and essential role in eliminating histoplasmosis (4) , tuberculosis, and strongyloidiasis infection (5).  We continued this line of investigation by evaluating the participation of leukotrienes in the immune protection induced by Cell-Free Antigens (CFAgs) against H. capsulatum infection. Our data strongly suggest that leukotrienes are essential to the immune protection induced by CFAg immunization. These findings contribute to a greater understanding of the role that leukotrienes play in host defense.

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2 FUNK C.. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science, 2001, 294, 1871.

3 KANAOKA Y., BOYCE JA.. Cysteinyl leukotrienes and their receptors: cellular distribution and function in immune and inflammatory responses. J. Immunol., 2004, 173, 1503.

4 MEDEIROS AI., SA-NUNES A., SOARES EG., PERES CM., SILVA CL., FACCIOLI LH.. Blockade of endogenous leukotrienes exacerbates pulmonary histoplasmosis.Infect. Immun., 2004, 72, 1637.

5 MACHADO ER., UETA MT., LOURENÇO EV., ANIBAL FF., SORGI CA., SOARES EG., ROQUE-BARREIRA MC., MEDEIROS AI., FACCIOLI LH.. Leukotrienes play a role in the control of parasite burden in murine strongyloidiasis. J. Immunol., 2005, 175, 3892.

6 LEWIS RA., AUSTEN KF., SOBERMAN RJ.. Leukotrienes and other products of the 5-lipoxygenase pathway. Biochemistry and relation to pathobiology in human diseases. N. Engl. J. Med., 1990, 323, 645-655.

7 MILLER DK., GILLARD JW., VICKERS PJ., SADOWSKI S., LEVEILLE C., MANCINI JA., CHARLESON P., DIXON RA., FORD-HUTCHINSON AW., FORTIN R., GAUTHIER JY., RODKEY J., ROSEN R., ROUZER C., SIGAL IS., STRADER CD., EVANS JF.. Identification and isolation of a membrane protein necessary for leukotriene production. Nature, 1990, 343, 278-81.

FINANCIAL SUPPORT: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

CORRESPONDENCE TO:

Lucia Helena Faccioli, Departamento de Análises Clínicas Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, USP, Avenida do Café s/n, Monte Alegre, 14040-903, Ribeirão Preto, SP, Brasil. Email: faccioli@fcfrp.usp.br