title: The role of the Annexin-A1/FPR2 system in the regulation of mast cell degranulation provoked by compound 48/80 and in the inhibitory action of nedocromil.
abstract: 1.We investigated the role of Annexin (ANX)-A1 and its receptor, ALX/FPR2, in the regulation of mast cell degranulation produced by compound 48/80. 2.Both human cord-blood derived mast cells (CBDMCs) and murine bone marrow derived mast cells (BMDMCs) release phosphorylated ANX-A1 during treatment with glucocorticoids or the mast cell 'stabilising' drugs ketotifen and nedocromil. 3.Compound 48/80 also stimulated ANX-A1 phosphorylation and release and this was also potentiated by nedocromil. Anti-ANX-A1 neutralising monoclonal antibodies (Mabs) enhanced the release of pro-inflammatory mediators in response to compound 48/80. 4.Nedocromil and ketotifen potently inhibited the release of histamine, PGD2, tryptase and β-hexosaminidase from mast cells challenged with compound 48/80. Anti-ANX-A1 neutralising Mabs prevented the inhibitory effect of these drugs. 5.BMDMCs derived from Anx-A1−/− mice were insensitive to the inhibitory effects of nedocromil or ketotifen but cells retained their sensitivity to the inhibitory action of hu-r-ANX-A1. 6.The fpr2/3 antagonist WRW4 blocked the action of nedocromil on PGD2, but not histamine, release. BMDMCs derived from fpr2/3−/− mice were insensitive to the inhibitory effects of nedocromil on PGD2, but not histamine release. 7.Compound 48/80 stimulated both p38 and JNK phosphorylation in CBDMCs and this was inhibited by nedocromil. Inhibition of p38 phosphorylation was ANX-A1 dependent. 8.We conclude that ANX-A1 is an important regulator of mast cell reactivity to compound 48/80 exerting a negative feedback effect through a mechanism that depends at least partly on the FPR receptor.
authors.affiliation: Centre for Biochemical Pharmacology, William Harvey Research Institute, St Barts and the Royal London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Ajantha
authors.initials: A
authors.lastname: Sinniah
authors.affiliation: Molecular Therapy Department, Institute of Ophthalmology, 11/14 Bath Street, London EC1V 9EL, UK.
authors.forename: Samia
authors.initials: S
authors.lastname: Yazid
authors.affiliation: Centre for Biochemical Pharmacology, William Harvey Research Institute, St Barts and the Royal London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: M
authors.initials: M
authors.lastname: Perretti
authors.affiliation: Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, St Barts and the Royal London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Egle
authors.initials: E
authors.lastname: Solito
authors.affiliation: Centre for Biochemical Pharmacology, William Harvey Research Institute, St Barts and the Royal London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address: r.j.flower@qmul.ac.uk.
authors.forename: R J
authors.initials: RJ
authors.lastname: Flower
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000378:metabolism*; D018926:Anti-Allergic Agents / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology; D015550:Cell Degranulation / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007665:Ketotifen / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects* / Q000502:physiology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017835:Nedocromil / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000378:metabolism*; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; D017305:Annexin A1; D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; C105101:FPR2 protein, human; D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C481578:formyl peptide receptor 2, mouse; D017835:Nedocromil; D003189:p-Methoxy-N-methylphenethylamine; D003907:Dexamethasone; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D007665:Ketotifen
keywords: ANX-A1; Compound 48/80; Cromones; Mast cell; PKC; PP2A