title: Shedding of membrane-bound CD14 from lipopolysaccharide-stimulated macrophages by vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide.
abstract: Macrophage activation and deactivation play essential roles in the initiation and maintenance of a successful immune response. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP), two structurally related neuropeptides, act as macrophage deactivating factors. We reported previously that VIP and PACAP inhibit IL-6, IL-12, TNF alpha and NO production, and enhance IL-10 production, from lipopolysaccharide (LPS)-stimulated macrophages. In this study, we demonstrate that VIP and PACAP down-regulate the expression of CD14, the membrane-bound LPS receptor, by inducing its rapid shedding. The soluble CD14 released by VIP and PACAP corresponds in size to the soluble CD14 released by PMA. Neither VIP/PACAP nor PMA, affect the steady-state levels of CD14 mRNA. The CD14 shedding induced by VIP/PACAP is mediated through the PAC1 specific receptors and the major transduction pathway involves the protein kinase C (PKC). The VIP/PACAP inhibition of TNF alpha and NO occurs through both CD14-dependent and -independent mechanisms, whereas the inhibition of IL-6 production appears to be strictly CD14-dependent. The shedding of CD14 by VIP and PACAP represents an important mechanism by which these neuropeptides limit the macrophage inflammatory response.
authors.affiliation: Departamento de Biologia Celular, Facultad de Biologia, Universidad Complutense, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Delgado
authors.forename: J
authors.initials: J
authors.lastname: Leceta
authors.forename: C
authors.initials: C
authors.lastname: Abad
authors.forename: C
authors.initials: C
authors.lastname: Martinez
authors.forename: D
authors.initials: D
authors.lastname: Ganea
authors.forename: R P
authors.initials: RP
authors.lastname: Gomariz
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D019476:Insect Proteins / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009479:Neuropeptides / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011493:Protein Kinase C / Q000378:metabolism; D018005:Receptors, Vasoactive Intestinal Peptide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: C495402:Adcyap1 protein, mouse; D019476:Insect Proteins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D009479:Neuropeptides; C110307:PG 97-269; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014409:Tumor Necrosis Factor-alpha; C069147:maxadilan protein, insect; D009569:Nitric Oxide; D014660:Vasoactive Intestinal Peptide; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate