Desensitization of chemokine receptor CCR5 in dendritic cells at the early stage of differentiation by activation of formyl peptide receptors.
Chemokine receptors are subjected to heterologous desensitization by activation of formyl peptide receptors. We investigated the cross-talk between formyl peptide receptors and the chemokine receptor CCR5 in human monocyte-differentiated immature dendritic cells (iDC). Monocytes cultured with GM-CSF and IL-4 for 4 days exhibit markers characteristic of iDC and maintain the expression of both formyl peptide receptors FPR and FPRL1, as well as CCR5. Pretreatment of iDC with W peptide (WKYMVm), a potent agonist for FPR and FPRL1 but with preference for FPRL1, resulted in down-regulation of CCR5 from the cell surface and reduced cell response to the CCR5 ligands through a PKC-dependent pathway. Furthermore, W peptide induced a PKC-dependent phosphorylation of CCR5 and inhibited infection of iDC by R5 HIV-1. Our results indicate that the expression and functions of CCR5 in iDC can be attenuated by W peptide, which activates formyl peptide receptors, and suggest an approach to the design of novel anti-HIV-1 agents.
Le
Y
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Laboratory of Molecular Immunoregulation, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
Wetzel
M A
MA
Shen
W
W
Gong
W
W
Rogers
T J
TJ
Henderson
E E
EE
Wang
J M
JM
D002454:Cell Differentiation; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000494:pharmacology; D003713:Dendritic Cells / Q000502:physiology* / Q000821:virology; D015536:Down-Regulation; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D010766:Phosphorylation; D019713:Receptors, CCR5 / Q000502:physiology*; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000502:physiology*; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide / Q000502:physiology*
D054407:Chemokine CCL4; D018946:Chemokine CCL5; C105101:FPR2 protein, human; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide