title: Catestatin, a neuroendocrine antimicrobial peptide, induces human mast cell migration, degranulation and production of cytokines and chemokines.
abstract: Catestatin, a neuroendocrine peptide with effects on human autonomic function, has recently been found to be a cutaneous antimicrobial peptide. Human catestatin exhibits three single nucleotide polymorphisms: Gly364Ser, Pro370Leu and Arg374Gln. Given reports indicating that antimicrobial peptides and neuropeptides induce mast cell activation, we postulated that catestatin might stimulate numerous functions of human mast cells, thereby participating in the regulation of skin inflammatory responses. Catestatin and its naturally occurring variants caused the human mast cell line LAD2 and peripheral blood-derived mast cells to migrate, degranulate and release leukotriene C(4) and prostaglandins D(2) and E(2). Moreover, catestatins increased intracellular Ca(2+) mobilization in mast cells, and induced the production of pro-inflammatory cytokines/chemokines such as granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein-1/CCL2, macrophage inflammatory protein-1α/CCL3 and macrophage inflammatory protein-1β/CCL4. Our evaluation of possible cellular mechanisms suggested that G-proteins, phospholipase C and the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) are involved in catestatin-induced mast cell activation as evidenced by the inhibitory effects of pertussis toxin (G-protein inhibitor), U-73122 (phospholipase C inhibitor) and U0126 (ERK inhibitor), respectively. We also found that human mast cells express the α7 subunit of the nicotinic acetylcholine receptor at both the mRNA and protein levels. Given that silencing the α7 receptor mRNA and an α7-specific inhibitor did not affect catestatin-mediated activation of mast cells, however, we concluded that this receptor is not likely to be functional in human mast cell stimulation by catestatins. Our finding that the neuroendocrine antimicrobial peptide catestatin activates human mast cells suggests that this peptide might have immunomodulatory functions, and provides a new link between neuroendocrine and cutaneous immune systems.
authors.affiliation: Atopy (Allergy) Research Centre, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Gyi
authors.initials: G
authors.lastname: Aung
authors.forename: François
authors.initials: F
authors.lastname: Niyonsaba
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ushio
authors.forename: Naoki
authors.initials: N
authors.lastname: Kajiwara
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Saito
authors.forename: Shigaku
authors.initials: S
authors.lastname: Ikeda
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D053379:Chromogranin A / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004963:Estrenes / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017997:Leukotriene C4 / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D034622:RNA Interference; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D023181:Antimicrobial Cationic Peptides; D018925:Chemokines; C579167:Chrna7 protein, human; D053379:Chromogranin A; D016207:Cytokines; D004963:Estrenes; D010446:Peptide Fragments; D011760:Pyrrolidinones; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C109084:chromogranin A (344-364); C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D017997:Leukotriene C4; D037342:Pertussis Toxin; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone; D015230:Prostaglandin D2; D002118:Calcium