The bacterial N-formylpeptides, such as N-formyl-Met-Leu-Phe (fMLF), are some of the first identified and most potent chemoattractants for phagocytic leukocytes. Two fMLF receptors, the high affinity formyl peptide receptor (FPR) and its low affinity variant FPR-like 1 (FPRL1), belong to the seven-transmembrane, Gi protein-coupled receptor superfamily which also includes chemokine receptors. Despite their reaction with bacterial chemotactic peptides, the physiological role of these receptors in humans remains unclear. Our recent studies have identified novel exogenous as well as host-derived agonists for FPR and FPRL1. Furthermore, activation of these receptors by their agonists results in desensitization of the receptors for other chemoattractants, including two chemokine receptors, CCR5 and CXCR4, which serve as major co-receptors for HIV-1. These results suggest that FPR and FPRL1 may play important roles not only in host defense and immunological responses but also in the fine tuning of cell activation in the presence of multiple stimuli.
FPRL1 is a seven-transmembrane (STM), G-protein coupled receptor which was originally identified as a low affinity receptor for the bacterial chemotactic formyl peptide and a high affinity receptor for the lipid metabolite lipoxin A4. We recently discovered that a number of peptides, including several synthetic domains of the HIV-1 envelope proteins and the serum amyloid A, use FPRL1 to induce migration and calcium mobilization in human monocytes and neutrophils. In this study, we report that a synthetic peptide domain of the V3 region of the HIV-1 envelope gp120, activates the FPRL1 receptor in monocytes and neutrophils. Furthermore, monocytes prestimulated with V3 peptide showed reduced response to several chemokines that use multiple cell receptors. This is associated with a rapid phosphorylation of the chemokine receptor CCR5 on the serine residues. Our study suggests that FPRL1, as a classical chemoattractant receptor, may play an important role in modulating monocyte activation in the presence of multiple stimuli.
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