Regulation of Neutrophil Activation by Proteolytic Processing of Platelet-Derived α-Chemokines
In recent years evidence has been accumulated that platelets besides their function in coagulation play an important role in inflammation and wound repair. Upon activation platelets release a variety of mediators, among which members of the α-chemokine subfamily of proinflammatory cytokines have been identified. These platelet-derived polypeptides do not only comprise members of the so-called ß-thromboglobulin family, such as platelet basic protein (PBP), connective tissue-activating peptide III (CTAP-III), and neutrophil-activating peptide 2 (NAP-2)1, but also platelet factor 4 (PF4)2,3 and the ß-chemokine RANTES (Regulated upon activation normal T cell expressed and probably secreted)4. While ß-chemokines have been shown to activate monocytes, T lymphocytes and eosinophils, α-chemokines such as IL-8, NAP-2 and melanoma growth-stimulating activity (MGSA/gro-α) appear to represent rather selective activators of polymorphonuclear leukocytes (PMN)5. Importantly, their biological activity, such as chemotaxis and degranulation-inducing capacity, has been demonstrated to be closely connected with the presence of an N-terminal glutamic acid-leucine-arginine (ELR) motif. Only recently, attention has been paid to the regulatory properties of α-chemokines. In the present article we will focus on two aspects of regulation of PMN functions, namely 1. the proteolytic processing of platelet-derived α-chemokines as a regulatory event in the induction and modulation of PMN activation, and 2. the phenotypic and functional consequences for the PMN under the constraints of such regulatory events.
KeywordsProteolytic Processing Neutrophil Activation Platelet Factor Inactive Precursor Elastase Release
Unable to display preview. Download preview PDF.
- 1.Brandt, E., H.-D. FIad: Structure and function of platelet-derived cytokines of the ß-thromboglobulin/interleukin 8 family. Platelets 3, 295, 1992Google Scholar
- 2.Niewiarowski, S., B. Rucinski, A. Z. Budzynski: Low affinity platelet factor 4 and high affinity platelet factor 4: two antiheparin factors secreted by human platelets. Thromb.Haemost. 42, 1679, 1979Google Scholar
- 9.Brandt, E., M. Ernst, H.-D. Flad: Enzymatic cleavage of CTAP-Ill from human platelets generates neutrophil-activating and anti-proliferative activities. In: Molecular and Cellular Biology of Cytokines (Eds.: J.J.Oppenheim, M.C.Powanda, M.J.Kluger, C.A.Dinarello), Wiley-Liss Inc., New York, pp. 357, 1990Google Scholar
- 16.Ehlert, J. E., F. Petersen, M. H. G. Kubbutat, J. Gerdes, H.-D. Flad, E. Brandt: Limited and defined truncation at the C terminus enhances receptor binding and degranulation activity of the neutrophil-activating peptide 2 (NAP-2). J.Biol. Chem. 270, 6338, 1995Google Scholar
- 17.Clark-Lewis, I., C. Schumacher, M. Baggiolini, B. Moser: Structure-activity relationships of interleukin-8 determined using chemically synthesized analogs. Critical role ofNH2-terminal residues and evidence for uncoupling of neutrophil chemotaxis, exocytosis, and receptor binding activities. J.Biol.Chem. 266, 23128, 1991PubMedGoogle Scholar
- 18.Petersen, F., H.-D. Flad, E. Brandt: Neutrophil-activating peptides NAP-2 and IL-8 bind to the same sites on neutrophils but interact in different ways. Discrepancies in binding affinities, receptor densities, and biologic effeccts. J.lmmunol. 152, 2467, 1994Google Scholar