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

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 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.

• Authors: Camila M Peres, David M Aronoff, Carlos H Serezani, Nicolas Flamand, Lucia H Faccioli, Marc Peters-Golden
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 179 Issue 8 Pg. 5454-61 (Oct 15 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17911632 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Leukotriene
• Toxoids
• pertussis toxoid
• Leukotriene B4
• Leukotriene D4
• Cyclic AMP
• GTP-Binding Proteins
• GTP-Binding Protein alpha Subunit, Gi2
• GTP-Binding Protein alpha Subunits, Gq-G11

Topics

• Animals
• Cells, Cultured
• Cyclic AMP (antagonists & inhibitors, metabolism)
• Down-Regulation (immunology)
• Female
• GTP-Binding Protein alpha Subunit, Gi2 (biosynthesis, genetics)
• GTP-Binding Protein alpha Subunits, Gq-G11 (biosynthesis, genetics)
• GTP-Binding Proteins (biosynthesis, metabolism, physiology)
• Intracellular Fluid (metabolism)
• Leukotriene B4 (antagonists & inhibitors, physiology)
• Leukotriene D4 (antagonists & inhibitors, physiology)
• Macrophage Activation (immunology)
• Macrophages, Alveolar (immunology, metabolism)
• Rats
• Rats, Wistar
• Receptors, Leukotriene (metabolism, physiology)
• Toxoids (pharmacology)