title: Physiological levels of interleukin-18 stimulate multiple neutrophil functions through p38 MAP kinase activation.
abstract: Patients with sepsis and acute lung injury have increased interleukin (IL)-18 levels systemically. We hypothesize that IL-18 stimulates neutrophils (PMNs) at physiologic concentrations. IL-18 primed the oxidase at 15 min (10-100 ng/ml), 30 min (0.1-100 ng/ml), and 60 min (100 ng/ml; P<0.05) and caused translocation of p47(phox) to the membrane similar to lipopolysaccharides. CD11b surface expression was increased by IL-18 in a time- and concentration-dependent manner. IL-18 caused up-regulation of the formyl-Met-Leu-Phe receptor, changes in PMN size, and elastase release. Investigation of signaling demonstrated IL-18-mediated activation of p38 mitogen-activated protein (MAP) kinase in a concentration (0.1-100 ng/ml)-, time (5-15 min)-, and Ca2+-dependent manner. IL-18 directly increased cytosolic Ca2+ concentration. IL-18 activation of PMNs was blocked by inhibition of p38 MAP kinase activity (SB203580) or by inhibition of p38 MAP kinase activation by chelation of cytosolic Ca2+. We conclude that IL-18, at physiologic concentrations, is an effective PMN priming agent that requires p38 MAP kinase activity.
authors.affiliation: Bonfils Blood Center, Denver, CO 80230, USA.
authors.forename: Travis H
authors.initials: TH
authors.lastname: Wyman
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Anirban
authors.initials: A
authors.lastname: Banerjee
authors.forename: Fabia
authors.initials: F
authors.lastname: Gamboni-Robertson
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Hiester
authors.forename: Kelly M
authors.initials: KM
authors.lastname: England
authors.forename: Marguerite
authors.initials: M
authors.lastname: Kelher
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Silliman
mesh_terms: D000328:Adult; D002118:Calcium; D020013:Calcium Signaling / Q000187:drug effects; D048429:Cell Size; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016177:Macrophage-1 Antigen / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D010750:Phosphoproteins / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics; D018000:Receptors, Peptide / Q000096:biosynthesis / Q000235:genetics; D016897:Respiratory Burst / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D002614:Chelating Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D020382:Interleukin-18; D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen; D008565:Membrane Proteins; D010750:Phosphoproteins; D011725:Pyridines; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D018000:Receptors, Peptide; C079789:neutrophil cytosol factor 67K; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D002118:Calcium