Effect of activated platelets on expression of cytokines in peripheral blood mononuclear cells – potential role of prostaglandin E₂

Summary

Platelets may act as inflammatory cells. To study the effects of soluble and cell-bound platelet factors on the expression of several cytokines and related mediators in leukocytes, peripheral blood mononuclear cells (PBMC) were incubated with platelet-free supernatants from SFLLRN-activated platelet-rich plasma (PRP) or SFLLRN-activated PRP in itself. Our main findings were: (i) the gene expression of several chemokines and some cytokines were markedly increased by both activated PRP and supernatants, as also confirmed at the protein level for IL-6, IL-8 and MIP-1α; (ii) the selective protein kinase A type I (PKAI) antagonist Rp-8-Br-cAMP reduced this platelet-induced expression of IL-6, IL-8 and MIP-1α in PBMC, suggesting a role of cAMP/PKAI mediated mechanisms in this interaction; (iii) PGE₂ dose-dependently increased the release of IL-6, IL-8 and MIP-1α from PBMC mimicking the effect of activated platelets. Furthermore, activated platelets released comparable amounts of PGE₂, suggesting that platelet-derived PGE₂ could interact with PBMC in co-cultures; (iv) IL-10 inhibited the platelet-inducing effect on IL-6, IL-8 and MIP-1α in PBMC, and notably, the addition PGE₂ totally abolished this IL-10 effect suggesting that the suppressive effect of IL-10 on the plateletinduced activation of PBMC might at least partly involve PGE₂related mechanisms. The present study supports a view of platelets as inflammatory cells, and suggests a potential role of platelet-derived PGE₂ in platelet-induced inflammatory responses.

Keywords

Platelets - inflammation - interleukin-6 - prostaglandin E₂ - mononuclear cells

• References

• 1 Klinger MHF. Platelets and inflammation. Anat Embryol 1997; 196: 1-11.
• 2 Clemetson KJ, Clemetson JM, Proudfoot AEI. et al. Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors in human platelets. Blood 2000; 96: 4046-54.
• 3 Aukrust P, Waehre T, Damas JK. et al. Inflammatory role of platelets in acute coronary syndromes. Heart 2001; 86: 605-6.
• 4 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 08: 1227-34.
• 5 Vincent JL, Yagushi A, Pradier O. Platelet function in sepsis. Crit Care Med 2002; 30: S513-S517.
• 6 Weyrich AS, McIntyre TM, McEver RP. et al. Monocyte tethering by P-selektin regulates monocyte chemotactic protein-1 and tumor necrosis factor-alpha secretion. Signal integration and NF-kappa B translocation. J Clin Invest 1995; 95: 2297-303.
• 7 Weyrich AS, Elstad MR, McEver RP. et al. Activated patelets signal chemokine ynthesis by human monocytes. J Clin Invest 1996; 97: 1525-34.
• 8 Taskén K, Hansson V, Aukrust P. et al. Protein kinase type 1 as a potential target for therapeutic intervention. Drugs News Perspect 2000; 13: 12-8.
• 9 Holme PA, Muller F, Solum NO. et al. Enhanced activation of platelets with abnormal release of RANTES in human immunodeficiency virus type 1 infection. FASEB J 1998; 12: 79-90.
• 10 Lindemann S, Tolley ND, Dixon DA. et al. Activated platelets mediate inflammatory signaling by regulated interleukin 1β synthesis. J Cell Biol 2001; 154: 485-90.
• 11 Yndestad A, Damås JK, Eiken HG. et al. Increased gene expression of tumor necrosis factor super family ligand in peripheral mononuclear cells during chronic heart failure. Cardiovasc Res 2002; 54: 175-82.
• 12 Yndestad A, Holm AM, Muller F. et al. Enhanced expression of inflammatory cytokines and activation markers in T-cells from patients with chronic heart failure. Cardiovasc Res 2003; 60: 141-6.
• 13 Naldini A, Pucci A, Carney DH. et al. Thrombin enhancement of interleukin-1 expression in mononuclear cells: involvement of proteinase-activated receptor-1. Cytokine 2002; 20: 191-9.
• 14 Iwahashi H, Takeshita A, Hanazawa S. Prostaglandin E2 stimulates AP-1-mediated CD14 expression in mouse macrophages via cyclic AMP-dependent protein kinase A. J Immunol 2000; 164: 5403-8.
• 15 Smith JB, Willis AL. Formation and release of prostaglandins by platelets in response to thrombin. Br J Pharmacol 1970; 40: 545P.
• 16 Tsuboi K, Sugimoto Y, Ichikawa A. Prostanoid receptor subtypes. Prostaglandins Other Lipid Mediat 2002; 68-9: 535-6.
• 17 Moore KL, de Waal Malefyt R, Coffman RL. et al. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001; 19: 683-65.
• 18 Holm AM, Aukrust P, Aandahl EM. et al. Impaired secretion of interleukin-10 by T cells from patients with common variable immunodeficiency – involvement of protein kinase A type I. J Immunol 2003; 170: 5772-7.
• 19 Mertz PM, DeWitt DL, Stetler-Stevenson WG. et al. Interleukin 10 suppression of monocyte prostaglandin H synthase-2. Mechanism of inhibition of prostaglandindependent matrix metalloproteinase production. J Biol Chem 1994; 269: 21322-9.
• 20 Rajeevan MS, Vernon SD, Taysavang N. et al. Validation of array-based gene expression profiles by real-time (kinetic) RT-PCR. J Mol Diagn 2001; 03: 26-31.
• 21 Neumann F-J, Marx N, Gawas M. et al. Induction of cytokine expression i leukocytes by binding og thrombin-stimulated platelets. Circulation 1997; 95: 2387-94.
• 22 Holm T, Damås JK, Holven K. et al. CXCchemokines in coronary artery disease: possible role of interactions between oxidized low-density lipoprotein, platelets and peripheral blood mononuclear cells. J Thromb Haemost 2003; 01: 257-62.
• 23 Papandicolaou DA. The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med 1998; 128: 127-37.
• 24 Adams DH, Lloyd AR. Chemokines: leucocyte recruitment and activation cytokines. Lancet 1997; 349: 490-5.
• 25 Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol 2001; 02: 108-15.
• 26 Damås JK, Gullestad L, Ueland T. et al. CXCchemokines, a new group of cytokines in cardiac heart failure-possible role of platelets and monocytes. Cardiovasc Res 2000; 45: 428-36.
• 27 Kassis S, Lee JC, Hanna N. Effects of prostaglandins and cAMP levels on monocyte IL-1 production. Agents Actions 1989; 27: 274-6.