Cutting edge: vasoactive intestinal peptide acts as a potent suppressor of inflammation in vivo by trans-deactivating chemokine receptors.
Chemokines mediate trafficking of leukocytes to sites of inflammation and immune responses through activation of G protein-coupled receptors, which thereby provide appealing targets for novel anti-inflammatory agents. Vasoactive intestinal peptide (VIP) is an immunosuppressive neurotransmitter. We show that VIP inhibited the function of chemokine receptors on monocytes and CD4(+) T lymphocytes, with impaired chemotaxis and calcium flux in response to the cognate chemokine ligands CXCL12, CCL3, CCL4, and CCL5. This was mediated by VIP receptor type 1 and was not caused by chemokine receptor internalization. However, VIP caused dose-dependent phosphorylation of the chemokine receptor CCR5. This trans-deactivation process was studied in a murine model of delayed-type hypersensitivity: continuous infusion of VIP resulted in significant abrogation of monocyte and lymphocyte infiltration. Circulating mononuclear cells from VIP-infused mice were unable to respond to chemokines. VIP may provide a novel approach to treatment of inflammatory diseases through inhibition of chemokine-dependent leukocyte recruitment.
Grimm
Michael C
MC
Department of Medicine, St. George Clinical School and. Inflammation Research Unit, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia. M.Grimm@unsw.edu.au
Newman
Rosie
R
Hassim
Zeenath
Z
Cuan
Natalia
N
Connor
Susan J
SJ
Le
Yingying
Y
Wang
Ji Ming
JM
Oppenheim
Joost J
JJ
Lloyd
Andrew R
AR
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002464:Cell Migration Inhibition; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004139:Dinitrofluorobenzene / Q000008:administration & dosage; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000473:pathology; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018005:Receptors, Vasoactive Intestinal Peptide / Q000502:physiology; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D015533:Transcriptional Activation / Q000276:immunology*; D014660:Vasoactive Intestinal Peptide / Q000008:administration & dosage* / Q000378:metabolism
D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D019707:Receptors, Chemokine; D018005:Receptors, Vasoactive Intestinal Peptide; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014660:Vasoactive Intestinal Peptide; D004139:Dinitrofluorobenzene