Vasoactive intestinal peptide dampens formyl-peptide-induced ROS production and inflammation by targeting a MAPK-p47phoxphosphorylation pathway in monocytes.
Reactive oxygen species (ROS) produced by the phagocyte NADPH oxidase (NOX2) are required for microbial clearance; however, when produced in excess they exacerbate inflammatory response and injure surrounding tissues. NOX2 is a multicomponent enzyme composed of membrane-associated cytochrome b588 and cytosolic components p47phox, p67phox, p40phox, and rac1/2. We investigated whether vasoactive intestinal peptide (VIP), an endogenous immune-modulatory peptide, could affect ROS production by NOX2 in primary human phagocytes. VIP did not modulate basal ROS production by phagocytes, but it inhibited monocyte and not neutrophil ROS production in response to the bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (fMLF). The action of VIP was essentially mediated by high-affinity G-protein coupled receptors VPAC1 as its specific agonist, [ALA11,22,28]VIP, mimicked VIP-inhibitory effect, whereas the specific VPAC1 antagonist, PG97-269, blunted VIP action. Further, we showed that VIP inhibited fMLF-induced phosphorylation of ERK1/2 (extracellular signal-regulated kinase 1/2), p38MAPK (p38 mitogen-activated protein kinase) pathways, and phosphorylation of p47phoxon Ser345 residue. Also, VIP exerted an anti-inflammatory effect in a model of carrageenan-induced inflammation in rats. We thus found that VIP exerts anti-inflammatory effects by inhibiting the "MAPK-p47phoxphosphorylation-NOX2 activation" axis. These data suggest that VIP acts as a natural anti-inflammatory agent of the mucosal system and its analogs could be novel anti-inflammatory molecules.
Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France.
P
P
Chedid
Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France.
T
T
Boussetta
Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France.
P M-C
PM
Dang
Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France.
S A
SA
Belambri
Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France.
V
V
Marzaioli
Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France.
M
M
Fasseau
Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France.|Service d'Anatomie et Cytologie Pathologique, Hopital Xavier Bichat, Paris, France.
F
F
Walker
Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France.
A
A
Couvineau
Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France.
J
J
El-Benna
Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France.
J-C
JC
Marie
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002351:Carrageenan; D002478:Cells, Cultured; D004487:Edema / Q000139:chemically induced / Q000276:immunology / Q000628:therapy*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000628:therapy*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D009000:Monocytes / Q000276:immunology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000276:immunology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014660:Vasoactive Intestinal Peptide / Q000627:therapeutic use*
D000893:Anti-Inflammatory Agents; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D014660:Vasoactive Intestinal Peptide; D009240:N-Formylmethionine Leucyl-Phenylalanine; D002351:Carrageenan; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D048049:Extracellular Signal-Regulated MAP Kinases