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Specific Leukotriene Receptors Couple to Distinct G Proteins to Effect Stimulation of Alveolar Macrophage Host Defense Functions¹

Camila M. Peres^*,, David M. Aronoff, Carlos H. Serezani^*, Nicolas Flamand^*, Lucia H. Faccioli and Marc Peters-Golden^2,*

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

Leukotrienes (LTs) are lipid mediators implicated in asthma and other inflammatory diseases. LTB₄ and LTD₄ also participate in antimicrobial defense by stimulating phagocyte functions via ligation of B leukotriene type 1 (BLT1) receptor and cysteinyl LT type 1 (cysLT1) receptor, respectively. Although both G_i and G_q proteins have been shown to be coupled to both BLT1 and cysLT1 receptors in transfected cell systems, there is little known about specific G protein subunit coupling to LT receptors, or to other G protein-coupled receptors, in primary cells. In this study we sought to define the role of specific G proteins in pulmonary alveolar macrophage (AM) innate immune responses to LTB₄ and LTD₄. LTB₄ but not LTD₄ reduced cAMP levels in rat AM by a pertussis toxin (PTX)-sensitive mechanism. Enhancement of FcR-mediated phagocytosis and bacterial killing by LTB₄ was also PTX-sensitive, whereas that induced by LTD₄ was not. LTD₄ and LTB₄ induced Ca²⁺ and intracellular inositol monophosphate accumulation, respectively, highlighting the role of G_q protein in mediating PTX-insensitive LTD₄ enhancement of phagocytosis and microbicidal activity. Studies with liposome-delivered G protein blocking Abs indicated a dependency on specific G_q/11 and G_i3 subunits, but not G_i2 or G, in LTB₄-enhanced phagocytosis. The selective importance of G_q/11 protein was also demonstrated in LTD₄-enhanced phagocytosis. The present investigation identifies differences in specific G protein subunit coupling to LT receptors in antimicrobial responses and highlights the importance of defining the specific G proteins coupled to heptahelical receptors in primary cells, rather than simply using heterologous expression systems.

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 HL078727 and HL058897 from the National Institutes of Health, by Grant RG-8909-N from the American Lung Association, and by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-Brazil). N.F. is the recipient of a postdoctoral award from the Canadian Institutes of Health Research.

² Address correspondence and reprint requests to Dr. Marc Peters-Golden, 6301 Medical Science Research Building III, Box 0642, University of Michigan Health System, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0642. E-mail address: petersm{at}umich.edu

³ Abbreviations used in this paper: LT, leukotriene; cysLT, cysteinyl LT; cysLT1, cysLT type 1; BLT1, BLT type 1; AM, alveolar macrophage; GPCR, G protein-coupled receptor; PLC, phospholipase C; PTX, pertussis toxin; IP1, inositol monophosphate.

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