title: Microbicidal protein psoriasin is a multifunctional modulator of neutrophil activation.
abstract: As effector cells in host defence, neutrophils actively destroy invading microorganisms via a potent antimicrobial arsenal composed of oxidants and antimicrobial peptides. Psoriasin, an Escherichia coli-cidal antimicrobial protein, has been found to be overexpressed in psoriasis, a skin disease characterized by infiltration of neutrophils. In addition to its microbicidal activities and chemotaxis of neutrophils reported previously, we hypothesized that psoriasin might regulate other neutrophil functions such as cytokine and chemokine production, reactive oxygen species generation, and release of antimicrobial peptides. In the current study, we demonstrate that psoriasin activates neutrophils to produce a range of cytokines and chemokines including interleukin-6 (IL-6), IL-8/CXCL8, tumour necrosis factor-alpha, macrophage inflammatory protein-1alpha (MIP-1alpha)/CCL3, MIP-1beta/CCL4 and MIP-3alpha/CCL20. Furthermore, psoriasin induces phosphorylation of mitogen-activated protein kinase p38 and extracellular signal-regulated kinase (ERK), but not c-Jun N-terminal kinase (JNK), both of which are required for the production of cytokines and chemokines as evidenced by the inhibitory effects of p38 and ERK inhibitors on psoriasin-mediated neutrophil activation. Moreover, psoriasin stimulates the generation of reactive oxygen species from neutrophils, most likely via nicotinamide adenine dinucleotide phosphate oxidase activation. Finally, we demonstrate that psoriasin enhances messenger RNA expression of alpha-defensins, termed human neutrophil peptides (HNP) 1 to 3, and induces their extracellular release. Besides its antimicrobial properties, therefore, psoriasin may contribute to innate immunity through enhancing neutrophil host defence functions at sites of inflammation or infection.
authors.affiliation: Department of Dermatology, Atopy Allergy Research Centre, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zheng
authors.forename: François
authors.initials: F
authors.lastname: Niyonsaba
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ushio
authors.forename: Shigaku
authors.initials: S
authors.lastname: Ikeda
authors.forename: Isao
authors.initials: I
authors.lastname: Nagaoka
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
mesh_terms: D017209:Apoptosis / Q000276:immunology; D002118:Calcium / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D015550:Cell Degranulation / Q000276:immunology; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D019255:NADPH Oxidases / Q000502:physiology; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; D015032:Zinc / Q000494:pharmacology; D023084:alpha-Defensins / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D018925:Chemokines; D016207:Cytokines; D017382:Reactive Oxygen Species; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human; D023084:alpha-Defensins; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015032:Zinc; D002118:Calcium