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

CM Peres, DM Aronoff, CH Serezani… - The Journal of …, 2007 - journals.aai.org
The Journal of Immunology, 2007journals.aai.org
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 Gα i and Gα 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 …
Abstract
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 Gα i and Gα 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 FcγR-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 Gα 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 Gα q/11 and Gα i3 subunits, but not Gα i2 or G β γ, in LTB 4-enhanced phagocytosis. The selective importance of Gα 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.
journals.aai.org