title: Acute-phase protein α1-antitrypsin inhibits neutrophil calpain I and induces random migration.
abstract: A rapid recruitment of neutrophils to sites of injury or infection is a hallmark of the inflammatory response and is required for effective host defense against pathogenic stimuli. However, neutrophil-mediated inflammation can also lead to chronic tissue destruction; therefore, a better understanding of the mechanisms underlying neutrophil influx and activation is of critical importance. We have previously shown that the acute phase protein α1-antitrypsin (AAT) inhibits neutrophil chemotaxis. In this study, we examine mechanisms related to the effect of AAT on neutrophil responses. We report a previously unknown function of AAT to inactivate calpain I (μ-calpain) and to induce a rapid cell polarization and random migration. These effects of AAT coincided with a transient rise in intracellular calcium, increase in intracellular lipids, activation of the Rho GTPases, Rac1 and Cdc42, and extra-cellular signal-regulated kinase (ERK1/2). Furthermore, AAT caused a significant inhibition of nonstimulated as well as formyl-met-leu-phe (fMLP)-stimulated neutrophil adhesion to fibronectin, strongly inhibited lipopolysaccharide-induced IL-8 release and slightly delayed neutrophil apoptosis. The results presented here broaden our understanding of the regulation of calpain-related neutrophil functional activities, and provide the impetus for new studies to define the role of AAT and other acute phase proteins in health and disease.
authors.affiliation: Department of Pulmonology, Hannover Medical School, Hannover, Germany.
authors.forename: Mariam
authors.initials: M
authors.lastname: Al-Omari
authors.forename: Elena
authors.initials: E
authors.lastname: Korenbaum
authors.forename: Matthias
authors.initials: M
authors.lastname: Ballmaier
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lehmann
authors.forename: Danny
authors.initials: D
authors.lastname: Jonigk
authors.forename: Dietmar J
authors.initials: DJ
authors.lastname: Manstein
authors.forename: Tobias
authors.initials: T
authors.lastname: Welte
authors.forename: Ravi
authors.initials: R
authors.lastname: Mahadeva
authors.forename: Sabina
authors.initials: S
authors.lastname: Janciauskiene
mesh_terms: D000199:Actins / Q000378:metabolism; D000209:Acute-Phase Proteins / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D017452:Receptors, IgG / Q000378:metabolism; D013049:Spectrin / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D000209:Acute-Phase Proteins; D016209:Interleukin-8; D017452:Receptors, IgG; D000515:alpha 1-Antitrypsin; D013049:Spectrin; D002784:Cholesterol; D048049:Extracellular Signal-Regulated MAP Kinases; D002154:Calpain; C449002:mu-calpain; D020741:rho GTP-Binding Proteins; D002118:Calcium