The neuropeptide pituitary adenylate cyclase activating polypeptide modulates Ca2+ and pro-inflammatory functions in human monocytes through the G protein-coupled receptors VPAC-1 and formyl peptide receptor-like 1.
In human neutrophils, the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) acting via the G protein-coupled receptors vasoactive intestinal peptide/PACAP receptor 1 (VPAC-1) and formyl peptide receptor-like 1 (FPRL1) modulates Ca2+ and pro-inflammatory activities. We evaluated in human monocytes the importance of the Ca2+ signal and the participation of FPRL1 in PACAP-associated signaling pathways and pro-inflammatory activities. PACAP-evoked Ca2+ transient involved both Ca2+ influx and intracytoplasmic Ca2+ mobilisation. This was pertussis toxin, protein kinase A and adenylate cyclase dependent indicating the participation of Galphai and Galphas with mobilisation of both InsP3 sensitive and insensitive stores. Intra- or extracellular Ca2+ depletion resulted in the inhibition of PACAP-induced, Akt, ERK, p38 and NF-kappaB activations as well as a decrease in PACAP-associated reactive oxygen species (ROS) production and integrin CD11b membrane upregulation. The FPRL1 antagonist, Trp-Arg-Trp-Trp-Trp (WRW4), decreased PACAP-evoked Ca2+ signal, Akt, ERK phosphorylation, ROS and CD11b upregulation without affecting p38 phosphorylation. NF-kappaB inhibitors prevented PACAP-induced Ca2+ mobilisation. Monocytes pre-treatment with fMLP but not with LPS desensitised cells to the pro-inflammatory effects of PACAP. Thus, both intra- and extracellular Ca2+ play a role in controlling pro-inflammatory functions stimulated by PACAP which acts through a VPAC-1, FPRL1/Galphai/PI3K/ERK pathway and a VPAC-1/Galphas/PKA/p38 pathway to fully activate monocytes.
El Zein
Nabil
N
Hemato-Oncology Unit and Laboratory of Pediatric Oncology, Hôpital Universitaire des Enfants, 1020 Brussels, Belgium.
Badran
Bassam
B
Sariban
Eric
E
D039481:CD11b Antigen / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000378:metabolism*; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000378:metabolism*; D016897:Respiratory Burst / Q000187:drug effects
D039481:CD11b Antigen; C105101:FPR2 protein, human; D016328:NF-kappa B; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs; D002118:Calcium