VIP differentially activates beta2 integrins, CR1, and matrix metalloproteinase-9 in human monocytes through cAMP/PKA, EPAC, and PI-3K signaling pathways via VIP receptor type 1 and FPRL1.
The neuropeptide vasoactive intestinal peptide (VIP) regulates the exocytosis of secretory granules in a wide variety of cells of neuronal and non-neuronal origin. In human monocytes, we show that the proinflammatory effects of VIP are associated with stimulation of exocytosis of secretory vesicles as well as tertiary (gelatinase) granules with, respectively, up-regulation of the membrane expression of the beta2 integrin CD11b, the complement receptor 1 (CD35), and the matrix metalloproteinase-9 (MMP-9). Using the low-affinity formyl peptide receptor-like 1 (FPRL1) antagonist Trp-Arg-Trp-Trp-Trp-Trp (WRW4) and the exchange protein directly activated by cAMP (EPAC)-specific compound 8CPT-2Me-cAMP and measuring the expression of Rap1 GTPase-activating protein as an indicator of EPAC activation, we found that the proinflammatory effect of VIP is mediated via the specific G protein-coupled receptor VIP/pituitary adenylate cyclase-activating protein (VPAC1) receptor as well as via FPRL1: VIP/VPAC1 interaction is associated with a cAMP increase and activation of a cAMP/p38 MAPK pathway, which regulates MMP-9, CD35, and CD11b exocytosis, and a cAMP/EPAC/PI-3K/ERK pathway, which regulates CD11b expression; VIP/FPRL1 interaction results in cAMP-independent PI-3K/ERK activation with downstream integrin up-regulation. In FPRL1-transfected Chinese hamster ovary-K1 cells lacking VPAC1, VIP exposure also resulted in PI-3K/ERK activation. Thus, the proinflammatory effects of VIP lie behind different receptor interactions and multiple signaling pathways, including cAMP/protein kinase A, cAMP/EPAC-dependent pathways, as well as a cAMP-independent pathway, which differentially regulates p38 and ERK MAPK and exocytosis of secretory vesicles and granules.
El Zein
Nabil
N
Hemato-Oncology Unit and Laboratory of Pediatric Oncology, Hôpital Universitaire des Enfants, Brussels, Belgium.
Badran
Bassam
B
Sariban
Eric
E
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000097:blood; D000818:Animals; D018821:CD18 Antigens / Q000187:drug effects / Q000502:physiology*; D016466:CHO Cells; D002118:Calcium / Q000502:physiology; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000097:blood*; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000097:blood; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D016133:Polymerase Chain Reaction; D017463:Receptors, Complement 3b / Q000187:drug effects / Q000502:physiology*; D044042:Receptors, Formyl Peptide / Q000097:blood*; D044067:Receptors, Lipoxin / Q000097:blood*; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000097:blood* / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
D018821:CD18 Antigens; C509991:CR1 protein, human; C105101:FPR2 protein, human; D017463:Receptors, Complement 3b; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014660:Vasoactive Intestinal Peptide; D004917:Erythromycin; C057513:erythromycin propionate-N-acetylcysteinate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020780:Matrix Metalloproteinase 9; D002118:Calcium; D000111:Acetylcysteine