The neuropeptide pituitary adenylate cyclase activating protein stimulates human monocytes by transactivation of the Trk/NGF pathway.
Transactivation is a process whereby stimulation of G-protein-coupled receptors (GPCR) activates signaling from receptors tyrosine kinase (RTK). In neuronal cells, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) acting through the GPCR VPAC-1 exerts trophic effects by transactivating the RTK TrkA receptor for the nerve growth factor (NGF). Both PACAP and NGF have pro-inflammatory activities on monocytes. We have tested the possibility that in monocytes, PACAP, as reported in neuronal cells, uses NGF/TrkA signaling pathway. In these cells, PACAP increases TrkA tyrosine phosphorylations through a PI-3kinase dependent but phospholipase C independent pathway. K252a, an inhibitor of TrkA decreases PACAP-induced Akt and ERK phosphorylation and calcium mobilisation resulting in decreases in intracellular H2O2 production and membrane upregulation of CD11b expression, both functions being inhibited after anti-NGF or anti-TrkA antibody treatment. K252a also inhibits PACAP-associated NF-KB activity. Monocytes increase in NGF production is seen after micromolar PACAP exposure while nanomolar treatment which desensitizes cells to high dose of PACAP prevents PACAP-induced TrkA phosphorylation, H2O2 production and CD11b expression. Finally, NGF-dependent ERK activation and H2O2 production is pertussis toxin sensitive. Altogether these data indicate that in PACAP-activated monocytes some pro-inflammatory activities occur through transactivation mechanisms involving VPAC-1, NGF and TrkA-associated tyrosine kinase activity.
El Zein
Nabil
N
Laboratory of Pediatric Oncology, Hôpital des Enfants, 1020 Brussels, Belgium.
Badran
Bassam M
BM
Sariban
Eric
E
D039481:CD11b Antigen / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D026121:Indole Alkaloids; D009000:Monocytes / Q000502:physiology*; D020932:Nerve Growth Factor / Q000502:physiology*; D010766:Phosphorylation; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000502:physiology*; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000502:physiology*; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation
D039481:CD11b Antigen; D002227:Carbazoles; D026121:Indole Alkaloids; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D020932:Nerve Growth Factor; C049985:staurosporine aglycone; D006861:Hydrogen Peroxide; D020917:Receptor, trkA; D048049:Extracellular Signal-Regulated MAP Kinases