Specific leukotriene receptors couple to distinct G proteins to effect stimulation of alveolar macrophage host defense functions.

Peres CM, Aronoff DM, Serezani CH, Flamand N, Faccioli LH, Peters-Golden M
J Immunol. 2007 179 (8): 5454-61

PMID: 17911632 · DOI:10.4049/jimmunol.179.8.5454

Leukotrienes (LTs) are lipid mediators implicated in asthma and other inflammatory diseases. LTB(4) and LTD(4) 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 Galpha(i) and Galpha(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 LTB(4) and LTD(4). LTB(4) but not LTD(4) reduced cAMP levels in rat AM by a pertussis toxin (PTX)-sensitive mechanism. Enhancement of FcgammaR-mediated phagocytosis and bacterial killing by LTB(4) was also PTX-sensitive, whereas that induced by LTD(4) was not. LTD(4) and LTB(4) induced Ca(2+) and intracellular inositol monophosphate accumulation, respectively, highlighting the role of Galpha(q) protein in mediating PTX-insensitive LTD(4) enhancement of phagocytosis and microbicidal activity. Studies with liposome-delivered G protein blocking Abs indicated a dependency on specific Galpha(q/11) and Galpha(i3) subunits, but not Galpha(i2) or G(beta)gamma, in LTB(4)-enhanced phagocytosis. The selective importance of Galpha(q/11) protein was also demonstrated in LTD(4)-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.

MeSH Terms (17)

Animals Cells, Cultured Cyclic AMP Down-Regulation Female GTP-Binding Protein alpha Subunit, Gi2 GTP-Binding Protein alpha Subunits, Gq-G11 GTP-Binding Proteins Intracellular Fluid Leukotriene B4 Leukotriene D4 Macrophage Activation Macrophages, Alveolar Rats Rats, Wistar Receptors, Leukotriene Toxoids

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