1.A novel biological effect of platelet factor 4 (PF4): enhancement of LPS-induced tissue factor activity in monocytes.
Engstad CS1, Lia K, Rekdal O, Olsen JO, Osterud B. J Leukoc Biol. 1995 Nov;58(5):575-81.
In a previous study we have shown that granulocytes enhance lipopolysaccharide (LPS)-induced tissue factor (TF) activity in monocytes in a platelet-dependent reaction. The present investigation was undertaken to examine the role of a platelet activation product, platelet factor 4 (PF4), in LPS-induced TF activity in monocytes. Platelet lysate supernatant, purified PF4, and the COOH-terminal tridecapeptide of PF4, termed PF4(58-70), enhanced LPS-induced TF activity in monocytes of whole blood dose dependently. A monoclonal antibody against P-selectin eliminated the enhancing effect of PF4(58-70) on LPS-induced TF activity in monocytes, and PF4(58-70) was shown to act synergistically with tumor necrosis factor alpha (TNF-alpha). However, PF4(58-70) did not enhance TNF-alpha secretion in LPS-stimulated whole blood. The major effect of PF4(58-70) was granulocyte dependent. Our results suggest that PF4 might play an important role in LPS-stimulated monocyte TF activity of whole blood.
2.Epinephrine promotes IL-8 production in human leukocytes via an effect on platelets.
Engstad CS1, Lund T, Osterud B. Thromb Haemost. 1999 Jan;81(1):139-45.
Interleukin-8 (IL-8) is generally accepted to be an important mediator of a number of acute and chronic inflammatory diseases and is produced by monocytes upon stimulation by lipopolysaccharide (LPS). Epinephrine has been reported by several groups to suppress activation of monocytes in response to LPS, and the aim of the present study was to examine the effect of epinephrine on LPS induced IL-8 production using whole blood as a model system. Epinephrine increased LPS induced IL-8 production in a dose-dependent manner in the whole concentration range (0.001-100 microM) and 1 microM epinephrine increased IL-8 levels with 125%. Epinephrine per se had no effect on IL-8 levels. The potentiating effect of epinephrine was mediated by blood platelets, since IL-8 levels in samples containing platelets and stimulated with LPS and epinephrine (1-100 microM) were significantly higher (p<0.05) than in control samples containing no platelets. This effect of platelets seemed to be due to platelet release products, since addition of 25 microL platelet lysate supernatant to whole blood increased LPS induced IL-8 production with 100% and a similar effect was observed in freshly isolated mononuclear cells resuspended in plasma.
3.Platelet factor 4 fragment induces histamine release from rat peritoneal mast cells.
Suzuki R1, Kimura T, Kitaichi K, Tatsumi Y, Matsushima M, Zhao YL, Shibata E, Baba K, Hasegawa T, Takagi K. Peptides. 2002 Oct;23(10):1713-7.
Platelet factor 4 (PF-4) belongs to a superfamily of low-molecular weight proteins known as chemokines. However, its function has not been fully evaluated. In the present study, we investigated the effect of PF-4 on histamine release from rat peritoneal mast cells by employing its biologically-active carboxyl-terminal fragment, PF-4 (58-70). PF-4 (58-70) stimulated histamine release from mast cells in a dose-dependent manner (10(-8) to 10(-5)M). Histamine release induced by PF-4 (58-70) occurred rapidly (<30s) and was inhibited by extracellular Ca(2+). These results suggest that PF-4 might play a crucial role at the site of inflammation and/or immune response.
4.Human platelet factor 4 and its C-terminal peptides: heparin binding and clearance from the circulation.
Rucinski B1, Niewiarowski S, Strzyzewski M, Holt JC, Mayo KH. Thromb Haemost. 1990 Jun 28;63(3):493-8.
Human platelet factor 4 (PF4), a high affinity heparin binding protein, is released from stimulated platelets and stored at vascular sites, predominantly in liver, from where it can be brought back into circulation by heparin. We attempted to define structural requirements for PF4 binding to heparin and for the pattern of its clearance from the circulation. Intact PF4 bound strongly to heparin agarose and was eluted at 1.4 M NaCl, while reduced PF4 and PF4 C-terminal peptides PF4 (47-70) and PF4 (58-70) bound weakly and were eluted at 0.2-0.5 M NaCl. 125I-radiolabeled intact PF4, reduced PF4 and C-terminal PF4 peptides injected into rabbits were cleared from the circulation in a biphasic pattern with components having half-life time of 1-2 min and 20-140 min. Heparin eliminated the fast component of PF4 clearance, but it did not affect clearance of reduced PF4 or C-terminal PF4 peptides. In contrast to reduced PF4 and PF4 (47-70), intact PF4 that accumulated in the liver and spleen, was displaced by heparin into circulating blood.
