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Thromb Haemost 2002; 88(02): 307-314
DOI: 10.1055/s-0037-1613203
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Transient Platelet Interaction Induces MCP-1 Production by Endothelial Cells via IκB Kinase Complex Activation

Meinrad Gawaz
1   1. Medizinische Klinik and Deutsches Herzzentrum, Klinikum rechts der Isar, Technische Universität München, Germany
,
Sharon Page
2   Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technische Universität München, Germany
,
Steffen Massberg
1   1. Medizinische Klinik and Deutsches Herzzentrum, Klinikum rechts der Isar, Technische Universität München, Germany
,
Caroline Nothdurfter
2   Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technische Universität München, Germany
,
Marion Weber
2   Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technische Universität München, Germany
,
Claudia Fischer
2   Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technische Universität München, Germany
,
Martin Ungerer
1   1. Medizinische Klinik and Deutsches Herzzentrum, Klinikum rechts der Isar, Technische Universität München, Germany
,
Korbinian Brand
2   Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technische Universität München, Germany
› Author Affiliations
Further Information

Publication History

Received 15 October 2001

Accepted after resubmission 06 May 2002

Publication Date:
07 December 2017 (online)

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Summary

Activated platelets alter endothelial chemotactic and adhesive properties. Transient interaction of α-thrombin-activated platelets with endothelial cells is sufficient to induce secretion of the NF-κBregulated chemokine MCP-1. To evaluate upstream signaling events in platelet-induced NF-κB activation, we compared the effect of platelets, IL-1β or TNF-α on IκB kinase (IKK) complex activation and IκB phosphorylation/proteolysis. Kinase assays demonstrated that platelets induced a slow increase in IKK activity over 30 min, which was similar, but not identical, to IL-1β, whereas TNF-α elicited a rapid induction of IKK. Differential effects were also found on IκB-α/ε degradation, while IKK levels were unaffected. Furthermore, overexpression of kinase-inactive IKK-βKA, as well as NIKKA, inhibited plateletor IL-1β-induced κB-, MCP-1or VCAM-1-dependent transcription. Using adeno-associated virus particles for cell transduction, we found that IKK-βKA substantially reduced stimulus-induced MCP-1 secretion. Platelet-induced signaling and resulting endothelial gene expression may play a role in early atherogenesis as well as plaque progression/destabilization.

Meinrad Gawaz, Sharon Page, and Steffen Massberg contributed equally to this work.

Keywords

Platelets - endothelium - NF-κB - IKK complex - adenoassociated virus
 

  • References

  • 1 Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med 1999; 340: 115-26.
    CrossrefPubMedSearch in Google Scholar
  • 2 Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA, Watson AD, Lusis AJ. Atherosclerosis: Basic mechanisms. Oxidation, inflammation and genetics. Circulation 1995; 91: 2488-96.
    CrossrefPubMedSearch in Google Scholar
  • 3 Kaplan JE, Moon DG, Weston LK, Minnear FL, Del Vecchio PJ, Shepard JM, Fenton JW. Platelets adhere to thrombin-treated endothelial cells in vitro . Am J Physiol 1989; 257: H423-33.
    PubMedSearch in Google Scholar
  • 4 Gawaz M, Neumann F-J, Dickfeld T, Reininger A, Adelsberger H, Gebhardt A, Schömig A. Vitronectin receptor (αvβ3) mediates platelet adhesion to the luminal aspect of endothelial cells. Implications for reperfusion in acute myocardial infarction. Circulation 1997; 96: 1809-18.
    CrossrefPubMedSearch in Google Scholar
  • 5 Bombeli T, Schwartz BR, Harlan JM. Adhesion of activated platelets to endothelial cells: Evidence for a GPIIb-IIIa-dependent bridging mechanism and novel roles for endothelial intercellular adhesion molecule-1 (ICAM1), αvβ3 integrin, and GPIbα. J Exp Med 1998; 187: 329-39.
    CrossrefPubMedSearch in Google Scholar
  • 6 Frenette PS, Denis CV, Weiss L, Jurk K, Subbaro S, Kehrel B, Hartwig JH, Vestweber D, Wagner DD. P-Selectin glycoprotein ligand-1 (PSGL-1) is expressed on platelets and can mediate platelet-endothelial interactions in vivo . J Exp Med 2000; 191: 1413-22.
    CrossrefPubMedSearch in Google Scholar
  • 7 Massberg S, Enders G, Leiderer R, Eisenmenger S, Vestweber D, Krombach F, Messmer K. Platelet-endothelial cell interactions during ischemia/reperfusion: the role of P-selectin. Blood 1998; 92: 507-12.
    PubMedSearch in Google Scholar
  • 8 Hawrylowicz CM, Howells GL, Feldmann M. Platelet-derived interleukin-1 induces human endothelial adhesion molecule expression and cytokine production. J Exp Med 1991; 174: 785-90.
    CrossrefPubMedSearch in Google Scholar
  • 9 Kaplanski G, Porat R, Aiura K, Erban JK, Gelfand JA, Dinarello CA. Activated platelets induce endothelial secretion of interleukin-8 in vitro via an interleukin-1-mediated event. Blood 1993; 81: 2492-95.
    PubMedSearch in Google Scholar
  • 10 Gawaz M, Brand K, Dickfeld T, Pogatsa-Murray G, Page S, Bogner C, Koch W, Schömig A, Neumann F-J. Platelets induce alterations of chemotactic and adhesive properties of endothelial cells mediated through an interleukin-1-dependent mechanism. Implications for atherogenesis. Atherosclerosis 2000; 148: 75-85.
    CrossrefPubMedSearch in Google Scholar
  • 11 Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Müller-Berghaus G, Kroczek RA. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391: 591-4.
    CrossrefPubMedSearch in Google Scholar
  • 12 Gawaz M, Neumann F-J, Dickfeld T, Koch W, Laugwitz KL, Adelsberger H, Langenbrink K, Page S, Neumeier D, Schömig A, Brand K. Activated platelets induce monocyte-chemotactic-protein-1 secretion and surface expression of intercellular adhesion molecule-1 on endothelial cells. Circulation 1998; 98: 1164-71.
    CrossrefPubMedSearch in Google Scholar
  • 13 Baeuerle PA, Baltimore D. NF-kappa B: ten years after. Cell 1996; 87: 13-20.
    CrossrefPubMedSearch in Google Scholar
  • 14 Baldwin AS. The NF-kappaB and IkappaB proteins: new discoveries and insights. Annu Rev Immunol 1996; 14: 649-83.
    CrossrefPubMedSearch in Google Scholar
  • 15 Thanos D, Maniatis T. NF-κB: A lesson in family values. Cell 1995; 80: 529-32.
    CrossrefPubMedSearch in Google Scholar
  • 16 Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol 2000; 18: 621-63.
    CrossrefPubMedSearch in Google Scholar
  • 17 Israël A. The IKK complex: an integrator of all signals that activate NF-kappaB?. Trends Cell Biol 2000; 10: 129-33.
    CrossrefPubMedSearch in Google Scholar
  • 18 Scheidereit C. Signal transduction. Docking IkappaB kinases. Nature 1998; 395: 225-6.
    CrossrefPubMedSearch in Google Scholar
  • 19 Dickfeld T, Lengyel E, May A, Massberg S, Brand K, Page S, Thielen C, Langenbrink K, Gawaz M. Transient interaction of activated platelets with endothelial cells induces expression of monocyte-chemoattractant-protein-1 via a p38 mitogen-activated protein kinase mediated pathway. Implications for atherogenesis. Cardiovasc Res 2001; 49: 189-99.
    CrossrefPubMedSearch in Google Scholar
  • 20 Brand K, Page S, Rogler G, Bartsch A, Brandl R, Knuechel R, Page M, Kaltschmidt C, Baeuerle PA, Neumeier D. Activated transcription factor nuclear factor-kappaB is present in the atherosclerotic lesion. J Clin Invest 1996; 97: 1715-22.
    CrossrefPubMedSearch in Google Scholar
  • 21 Fischer C, Page S, Weber M, Eisele T, Neumeier D, Brand K. Differential effects of lipopolysaccharide and tumor necrosis factor on monocytic IkappaB kinase signalsome activation and IkappaB proteolysis. J Biol Chem 1999; 274: 24625-32.
    CrossrefPubMedSearch in Google Scholar
  • 22 Ueda A, Ishigatsubo Y, Okubo T, Yoshimura T. Transcriptional regulation of the human monocyte-chemoattractant-protein-1 gene. Cooperation of two NF-κB sites and NF-κB/Rel subunit specificity. J Biol Chem 1997; 272: 31092-9.
    CrossrefPubMedSearch in Google Scholar
  • 23 Zolotukhin S, Byrne BJ, Mason E, Zolotukhin I, Potter M, Chesnut K, Summerford C, Samulski RJ, Muzyczka N. Recombinant adeno-associated-virus purification using novel methods improves infectious titer and yield. Gene Ther 1999; 06: 973-85.
    CrossrefPubMedSearch in Google Scholar
  • 24 Grimm D, Kleinschmidt JA. Progress in adeno-associated-virus type-2 vector production: promises and prospects for clinical use. Hum Gene Ther 1999; 10: 2445-50.
    CrossrefPubMedSearch in Google Scholar
  • 25 Hermens WT, ter OBrake, Dijkhuizen PA, Sonnemans MA, Grimm D, Kleinschmidt JA, Verhaagen J. Purification of recombinant adeno-associated-virus by iodixanol gradient ultracentrifugation allows rapid and reproducible preparation of vector stocks for gene transfer in the nervous system. Hum Gene Ther 1999; 10: 1885-91.
    CrossrefPubMedSearch in Google Scholar
  • 26 Hauswirth WW, Lewin AS, Zolotukhin S, Muzyczka N. Production and purification of recombinant adeno-associated-virus. Methods Enzymol 2000; 316: 743-61.
    PubMedSearch in Google Scholar
  • 27 Turitto VT, Goldsmith HL. Rheology, transport and thrombosis in the circulation. In: Vascular Medicine. Loscalzo J, Creager M, Dzau V, Chobanian A. eds. Boston: Little, Brown and Company; 1996: 141-84.
    Search in Google Scholar
  • 28 Lu B, Rutledge BJ, Gu L, Fiorillo J, Lukacs NW, Kunkel SL, North R, Gerard C, Rollins BJ. Abnormalities in monocyte recruitment and cytokine expression in monocyte-chemoattractant-protein-1-deficient mice. J Exp Med 1998; 187: 601-8.
    CrossrefPubMedSearch in Google Scholar
  • 29 Neiken NA, Coughlin SR, Gordon D, Wilcox JN. Monocyte-chemoattractant-protein-1 in human atherosclerotic plaques. J Clin Invest 1991; 88: 1121-7.
    CrossrefPubMedSearch in Google Scholar
  • 30 Mackman N. Regulation of tissue factor gene expression in human monocytic and endothelial cells. Haemostasis 1996; 26S1: 17-9.
    PubMedSearch in Google Scholar
  • 31 Collins T. Endothelial nuclear factor κB and the initiation of the atherosclerotic lesion. Lab Invest 1993; 68: 499-508.
    PubMedSearch in Google Scholar
  • 32 Siess W. Molecular mechanisms of platelet activation. Physiol Rev 1989; 69: 158-78.
    PubMedSearch in Google Scholar
  • 33 Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends in Cell Biology 2001; 11: 372-7.
    CrossrefPubMedSearch in Google Scholar
  • 34 Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ. Pro-inflammatory cytokines and environmental stress cause p38 mitogenactivated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem 1995; 270: 7420-6.
    CrossrefPubMedSearch in Google Scholar
  • 35 Ridley SH, Sarsfield SJ, Lee JC, Bigg HF, Cawston TE, Taylor DJ, DeWitt DL, Saklatvala J. Actions of IL-1 are selectively controlled by p38 mitogenactivated protein kinase: regulation of prostaglandin-H-synthase-2, metalloproteinases, and IL-6 at different levels. J Immunol 1997; 158: 3165-73.
    PubMedSearch in Google Scholar
  • 36 Lynch CM, Hara PS, Leonard JC, Williams JK, Dean RH, Geary RL. Adeno-associated-virus vectors for vascular gene delivery. Circ Res 1997; 80: 497-505.
    PubMedSearch in Google Scholar
  • 37 Weber KS, Draude G, Erl W, de Martin R, Weber C. Monocyte arrest and transmigration on inflamed endothelium in shear flow is inhibited by adenovirus-mediated gene transfer of IkappaB-alpha. Blood 1999; 93: 3685-93.
    PubMedSearch in Google Scholar