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Neutrophil Apoptosis: Selective Regulation by Different Ligands of Integrin _Mβ₂¹

Elzbieta Pluskota^*, Dmitry A. Soloviev^*, Dorota Szpak^*, Christian Weber and Edward F. Plow^2,*

^* Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, OH 44195; and Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany

Neutrophils undergo spontaneous apoptosis, but their survival can be extended during inflammatory responses. _Mβ₂ is reported either to delay or accelerate neutrophil apoptosis, but the mechanisms by which this integrin can support such diametrically opposed responses are poorly understood. The abilities of closely related _Mβ₂ ligands, plasminogen and angiostatin, derived from plasminogen, as well as fibrinogen and its two derivative _Mβ₂ recognition peptides, P1 and P2-C, differed markedly in their effects on neutrophil apoptosis. Plasminogen, fibrinogen, and P2-C suppressed apoptosis via activation of Akt and ERK1/2 kinases, while angiostatin and P1 failed to activate these prosurvival pathways and did not prevent neutrophil apoptosis. Using cells transfected with _Mβ₂ or its individual _M or β₂ subunits, and purified receptors and its constituent chains, we show that engagement of both subunits with prosurvival ligands is essential for induction of the prosurvival response. Hence, engagement of a single integrin by closely related ligands can induce distinct signaling pathways, which can elicit distinct cellular responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by National Institutes of Health Grant R01 HL17964 and P50 HL 081011 (E.F.P.) and by an American Heart Association Scientist Development Grant (E.P.).

² Address correspondence and reprint requests to Dr. Edward F. Plow, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, NB50, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail address: plowe{at}ccf.org

³ Abbreviations used in this paper: PMN, polymorphonuclear leukocyte; Ang(1–4), angiostatin composed of four kringle domains; BDM, 2,3-butanedione 2-monoxime; Fg, fibrinogen; H7, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride; MFI, mean fluorescence intensity; MLCK, myosin L chain kinase; NIF, neutrophil inhibitory factor; MβCD, methyl-β-cyclodextrin; PI, propidium iodide; Plg, plasminogen; Plm, plasmin; PVP, polyvinylpyrrolidone; RFU, relative fluorescence units.