Regulation of human polymorphonuclear leukocytes functions by the neuropeptide pituitary adenylate cyclase-activating polypeptide after activation of MAPKs.
Anti-inflammatory activities of pituitary adenylate cyclase-activating protein (PACAP) are mediated in part through specific effects on lymphocytes and macrophages. This study shows that in human polymorphonuclear neutrophils (PMNs), PACAP acts as a proinflammatory molecule. In PMNs, vaso-intestinal peptide/PACAP receptor 1 (VPAC-1) was the only receptor found to be expressed by RT-PCR. Using VPAC-1 Ab, we found that VPAC-1 mRNA was translated into proteins. In PMNs, PACAP increases cAMP, inositol triphosphate metabolites, and calcium. It activates two of the three members of the MAPK superfamily, the ERK and the stress-activated MAPK p38. U73122, an inhibitor of phospholipase C (PLC), inhibits PACAP-induced ERK activation, whereas p38 MAPK phosphorylation was unaffected. Using specific pharmalogical inhibitors of ERK (PD098059) and p38 MAPK (SB203580), we found that PACAP-mediated calcium increase was ERK and PLC dependent and p38 independent. PACAP primes fMLP-associated calcium increase; it also primes fMLP activation of the respiratory burst as well as elastase release, these last two processes being ERK and PLC dependent and p38 MAPK independent. PACAP also increases membrane expression of CD11b and release of lactoferrin and metallo proteinase-9 (MMP-9). These effects were PLC dependent (CD 11b, lactoferrin, MMP-9), ERK dependent (CD 11b, lactoferrin, MMP-9), and p38 dependent (CD11b, lactoferrin). We conclude that PACAP is a direct PMN activator as well as an effective PMN priming agent that requires PLC, ERK, and p38 MAPK activities.
Harfi
Issam
I
Hemato-Oncology Unit and Laboratory of Pediatric Oncology, Hôpital Universitaire des Enfants, Hôpital Brugman, Brussels, Belgium.
D'Hondt
Stéphanie
S
Corazza
Francis
F
Sariban
Eric
E
D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000502:physiology; D039481:CD11b Antigen / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007781:Lactoferrin / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009479:Neuropeptides / Q000378:metabolism / Q000502:physiology*; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018005:Receptors, Vasoactive Intestinal Peptide / Q000096:biosynthesis; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D016897:Respiratory Burst / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D010738:Type C Phospholipases / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases
C495401:ADCYAP1 protein, human; D000276:Adjuvants, Immunologic; D039481:CD11b Antigen; D018836:Inflammation Mediators; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018005:Receptors, Vasoactive Intestinal Peptide; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D007781:Lactoferrin; D010196:Pancreatic Elastase; D020780:Matrix Metalloproteinase 9; D002118:Calcium