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Gene Review

PF4  -  platelet factor 4

Homo sapiens

Synonyms: C-X-C motif chemokine 4, CXCL4, Iroplact, Oncostatin-A, PF-4, ...
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Disease relevance of PF4

  • Pertussis toxin did not block the PF4-derived IL-8 production in NK cells, but this response was sensitive to wortmannin, implicating a role of phosphatidylinositol 3-kinase in the intracellular signaling pathway triggered by PF4 [1].
  • Plasma levels of PF4, beta TG, TAT, FPA and D-dimer, but not PIC, in patients with Takayasu's arteritis were substantially higher than those in normal control subjects [2].
  • RESULTS: BTG was detected in 11 of the patients with systemic sclerosis (29.7%) and PF4 was found in eight (21.6%) [3].
  • The effect of human platelet factor 4 (PF4) and beta-thromboglobulin (BTG) on megakaryocyte colony formation in normal subjects as well as in essential thrombocythaemia (ET) and in immune thrombocytopenic purpura (ITP) was studied [4].
  • Previous data have demonstrated that CXC-chemokine platelet factor 4 (PF4) inhibits the proliferation of the human erythroleukemia cell line (HEL) [5].

Psychiatry related information on PF4

  • In the whole group of the 53 patients there was no significant alteration in platelet-specific proteins during exercise, whereas physical activity induced a 2- to 3-fold increase in beta-TG and PF4 levels in the controls [6].

High impact information on PF4

  • Human platelet factor 4 (PF4) is known to bind to heparin and inhibit its anticoagulant effect [7].
  • Here, we describe a distinct, previously unrecognized receptor named CXCR3-B, derived from an alternative splicing of the CXCR3 gene that mediates the angiostatic activity of CXCR3 ligands and also acts as functional receptor for CXCL4 [8].
  • By contrast, only minimal if any effects were obtained with PBP, CTAP-III, and PF-4 up to 100 nM [9].
  • Purified PF 4 also inhibited the basal incorporation of [3H]thymidine into 3T3 fibroblasts and the increased [3H]thymidine incorporation occurring after wounding of a cell monolayer [10].
  • These results indicate that an important role of PF 4 released at sites of vascular injury and platelet activation is to control cellular proliferation caused by the release of bFGF from ruptured cells [10].

Chemical compound and disease context of PF4


Biological context of PF4

  • We first corroborated our initial studies by showing that recombinant human (rH) PF4, like the native protein, inhibited megakaryocytopoiesis [16].
  • Thus, these studies demonstrate that the novel TME binding transcription factors, USF1 and 2, transactivate rat and human PF4 promoters and may play an important role in megakaryocytic gene expression [17].
  • We conclude that PF4 has the capacity to influence hematopoiesis through mechanisms not mediated by a classical high-affinity, 7-transmembrane domain chemokine receptor [18].
  • The activated partial thromboplastin time (APTT; baseline, 28 seconds) increased maximally by 27 +/- 6 seconds in PF4-treated animals and by 9 +/- 1 seconds in control animals at 30 minutes (P <.001) [19].
  • Interestingly, the E-box motif in the TME was conserved in TME-like sequences of both the human and mouse PF4 promoters [17].

Anatomical context of PF4

  • We introduced the ELR sequence at the N terminus of PF4 and found that the modified protein was a potent neutrophil activator and attractant [20].
  • Thus, physiologically relevant concentrations of PF4 stimulate thrombin-dependent APC generation both in vitro by cultured endothelial cells and in vivo in a primate thrombin infusion model [19].
  • Pretreatment of CD34+ cells by PF4, but not by TGFbeta1, caused an increase in the number of megakaryocyte colonies after these cells were replated in secondary cultures [21].
  • The effects of platelet factor 4 (PF4) on the viability and chemosensitivity of normal hematopoietic cells and cancer cell lines were studied to determine the mechanisms whereby PF4 functions as either an inhibitor or a protector and to evaluate its clinical significance [21].
  • APC generated in the presence of 1 to 100 microg PF4 was up to 5-fold higher than baseline for human umbilical vein endothelial cells, 10-fold higher for microvascular endothelial cells, and unaltered for blood outgrowth endothelial cells [19].

Associations of PF4 with chemical compounds

  • Protamine sulfate at 1 to 100 microg/mL showed no such activity of PF4 [21].
  • Instead, PF4 may modulate the hematopoietic milieu both directly, by promoting progenitor adhesion and quiescence through interaction with an HPC chondroitin sulfate-containing moiety, and indirectly, by binding to or interfering with signaling caused by other, hematopoietically active chemokines, such as IL-8 [18].
  • Since PF4 mutants lacking a heparin binding ability retain their anti-angiogenic activity, alternative inhibitory mechanisms were also examined [22].
  • Functionally, DC developed in the presence of PF4 had their secretion of tumor necrosis factor-alpha and IL-12 reduced by 75 +/- 10 and 79 +/- 13% respectively when they were stimulated by 100 ng/ml lipopolysaccharide and 50 ng/ml IFN-gamma [23].
  • BTG and PF4 release from blood anticoagulated with sodium citrate was inhibited by AD6 during a 3 h incubation [24].

Physical interactions of PF4

  • Surface plasmon resonance analysis shows that PF4 binds IL-8 with high (dissociation constant [Kd] = 42 nM) affinity [18].
  • Competition experiments showed that serglycin was as efficient as heparin sulfate in blocking the binding of [3H] chondrotin sulfate to PF4, whereas heparin was one order of magnitude more efficient [25].
  • Thus, the beta TG/PF4 genes appear to form a close-linked complex expressed in a megakaryocyte-specific fashion [26].
  • We find that PF4 binds to human CD34+ hematopoietic progenitor cells (HPCs) with a median effective concentration of 1 microg/mL but not after exposure to chondroitinase ABC [18].
  • These results show that CXCR2 selective receptor antagonists can be generated based upon the secondary binding determinants of GROalpha and PF4 [27].

Regulatory relationships of PF4

  • Immunophenotypically, monocyte-derived DC in the presence of increasing concentrations of PF4 proportionally expressed higher CD86 and lower HLA-DR [23].
  • The signaling transduction induced by PF4 in the HEL was compared with that induced by transforming growth factor beta1 (TGF-beta1), which is also a potent inhibitor of HEL growth [5].
  • In contrast, VEGF(165)-induced phosphorylation of KDR and PLCgamma was partially inhibited by PF-4 [28].
  • PF4 dramatically decreased the transient rise of [Ca2+] and protein kinase C (PKC) activity of HEL cells induced by IL-3 [5].
  • Furthermore, PF4 was found to down-regulate significantly protein tyrosine kinase (PTK) activity [5].
  • Taken together, PF4-stimulated immediate monocyte functions (oxygen radical formation) are regulated by p38 MAPK, Syk, and PI3K, whereas delayed functions (survival and cytokine expression) are controlled by Erk and JNK [29].

Other interactions of PF4

  • Platelet factor 4 (PF4) is structurally related to IL-8 (35% sequence identity) but lacks the N-terminal ELR sequence and comparable effects on neutrophils [20].
  • We have previously shown that platelet factor 4 (PF4), a platelet-specific CXC chemokine, can directly and specifically inhibit human megakaryocyte colony formation [16].
  • Both of these latter two genes have been previously reported to be duplicated, there being a PF4 and a PF4alt gene, and a beta TG1 and beta TG2 gene [26].
  • Flow cytometry analysis showed that when CD34+ cells were preincubated with PF4 or TGFbeta1 for 12 days in hematopoietic growth factor-rich medium, an increased number of remaining CD34+ cells was observed only for PF4-treated cells [21].
  • NAP-2, PF-4, and MCP-1 did not affect actin polymerization [30].

Analytical, diagnostic and therapeutic context of PF4


  1. Platelet factor 4 induces human natural killer cells to synthesize and release interleukin-8. Martí, F., Bertran, E., Llucià, M., Villén, E., Peiró, M., Garcia, J., Rueda, F. J. Leukoc. Biol. (2002) [Pubmed]
  2. Hypercoagulable state in patients with Takayasu's arteritis. Akazawa, H., Ikeda, U., Yamamoto, K., Kuroda, T., Shimada, K. Thromb. Haemost. (1996) [Pubmed]
  3. Beta thromboglobulin and platelet factor 4 in bronchoalveolar lavage fluid of patients with systemic sclerosis. Kowal-Bielecka, O., Kowal, K., Lewszuk, A., Bodzenta-Lukaszyk, A., Walecki, J., Sierakowski, S. Ann. Rheum. Dis. (2005) [Pubmed]
  4. Negative regulation of human megakaryocytopoiesis by human platelet factor 4 and beta thromboglobulin: comparative analysis in bone marrow cultures from normal individuals and patients with essential thrombocythaemia and immune thrombocytopenic purpura. Han, Z.C., Bellucci, S., Tenza, D., Caen, J.P. Br. J. Haematol. (1990) [Pubmed]
  5. Signal transduction of chemokine platelet factor 4 in human erythroleukemia cells. Liu, Y.J., Lu, S.H., Han, Z.C. Int. J. Hematol. (2002) [Pubmed]
  6. Exercise induces in vivo platelet activation in patients with coronary artery disease and in healthy individuals. Schernthaner, G., Mühlhauser, I., Böhm, H., Seebacher, C., Laimer, H. Haemostasis (1983) [Pubmed]
  7. Platelet factor 4: an inhibitor of collagenase. Hiti-Harper, J., Wohl, H., Harper, E. Science (1978) [Pubmed]
  8. An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4. Lasagni, L., Francalanci, M., Annunziato, F., Lazzeri, E., Giannini, S., Cosmi, L., Sagrinati, C., Mazzinghi, B., Orlando, C., Maggi, E., Marra, F., Romagnani, S., Serio, M., Romagnani, P. J. Exp. Med. (2003) [Pubmed]
  9. Effects of the neutrophil-activating peptide NAP-2, platelet basic protein, connective tissue-activating peptide III and platelet factor 4 on human neutrophils. Walz, A., Dewald, B., von Tscharner, V., Baggiolini, M. J. Exp. Med. (1989) [Pubmed]
  10. Platelet factor 4 modulates the mitogenic activity of basic fibroblast growth factor. Watson, J.B., Getzler, S.B., Mosher, D.F. J. Clin. Invest. (1994) [Pubmed]
  11. Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia. Rauova, L., Poncz, M., McKenzie, S.E., Reilly, M.P., Arepally, G., Weisel, J.W., Nagaswami, C., Cines, D.B., Sachais, B.S. Blood (2005) [Pubmed]
  12. Platelet activation in muscle contraction headache and migraine. Takeshima, T., Shimomura, T., Takahashi, K. Cephalalgia : an international journal of headache. (1987) [Pubmed]
  13. beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) in obstetrical cases. Arocha-Piñango, C.L., Ojeda, A., López, G., García, L., Linares, J. Acta obstetricia et gynecologica Scandinavica. (1985) [Pubmed]
  14. Platelet specific proteins (beta-thromboglobulin and platelet factor 4) in normal pregnancy and in pregnancy complicated by preeclampsia. Csaicsich, P., Deutinger, J., Tatra, G. Arch. Gynecol. Obstet. (1989) [Pubmed]
  15. The evidence of platelet activation in bronchial asthma. Yamamoto, H., Nagata, M., Tabe, K., Kimura, I., Kiuchi, H., Sakamoto, Y., Yamamoto, K., Dohi, Y. J. Allergy Clin. Immunol. (1993) [Pubmed]
  16. Chemokine regulation of human megakaryocytopoiesis. Gewirtz, A.M., Zhang, J., Ratajczak, J., Ratajczak, M., Park, K.S., Li, C., Yan, Z., Poncz, M. Blood (1995) [Pubmed]
  17. Upstream stimulatory factors stimulate transcription through E-box motifs in the PF4 gene in megakaryocytes. Okada, Y., Matsuura, E., Tozuka, Z., Nagai, R., Watanabe, A., Matsumoto, K., Yasui, K., Jackman, R.W., Nakano, T., Doi, T. Blood (2004) [Pubmed]
  18. Platelet factor 4 promotes adhesion of hematopoietic progenitor cells and binds IL-8: novel mechanisms for modulation of hematopoiesis. Dudek, A.Z., Nesmelova, I., Mayo, K., Verfaillie, C.M., Pitchford, S., Slungaard, A. Blood (2003) [Pubmed]
  19. Platelet factor 4 enhances generation of activated protein C in vitro and in vivo. Slungaard, A., Fernandez, J.A., Griffin, J.H., Key, N.S., Long, J.R., Piegors, D.J., Lentz, S.R. Blood (2003) [Pubmed]
  20. Platelet factor 4 binds to interleukin 8 receptors and activates neutrophils when its N terminus is modified with Glu-Leu-Arg. Clark-Lewis, I., Dewald, B., Geiser, T., Moser, B., Baggiolini, M. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  21. Platelet factor 4 and other CXC chemokines support the survival of normal hematopoietic cells and reduce the chemosensitivity of cells to cytotoxic agents. Han, Z.C., Lu, M., Li, J., Defard, M., Boval, B., Schlegel, N., Caen, J.P. Blood (1997) [Pubmed]
  22. Platelet factor-4 inhibits the mitogenic activity of VEGF121 and VEGF165 using several concurrent mechanisms. Gengrinovitch, S., Greenberg, S.M., Cohen, T., Gitay-Goren, H., Rockwell, P., Maione, T.E., Levi, B.Z., Neufeld, G. J. Biol. Chem. (1995) [Pubmed]
  23. Effect of CXC chemokine platelet factor 4 on differentiation and function of monocyte-derived dendritic cells. Xia, C.Q., Kao, K.J. Int. Immunol. (2003) [Pubmed]
  24. Action of AD6 (8-monochloro-3-beta-diethylaminoethyl-4-methyl-7-ethoxycarbonylmet hox y coumarin) on human platelets in vitro. Prosdocimi, M., Zatta, A., Gorio, A., Zanetti, A., Dejana, E. Naunyn Schmiedebergs Arch. Pharmacol. (1986) [Pubmed]
  25. Serglycin-binding proteins in activated macrophages and platelets. Kolset, S.O., Mann, D.M., Uhlin-Hansen, L., Winberg, J.O., Ruoslahti, E. J. Leukoc. Biol. (1996) [Pubmed]
  26. Genes for beta-thromboglobulin and platelet factor 4 are closely linked and form part of a cluster of related genes on chromosome 4. Tunnacliffe, A., Majumdar, S., Yan, B., Poncz, M. Blood (1992) [Pubmed]
  27. Chemokine antagonists that discriminate between interleukin-8 receptors. Selective blockers of CXCR2. Jones, S.A., Dewald, B., Clark-Lewis, I., Baggiolini, M. J. Biol. Chem. (1997) [Pubmed]
  28. Platelet factor 4 disrupts the intracellular signalling cascade induced by vascular endothelial growth factor by both KDR dependent and independent mechanisms. Sulpice, E., Contreres, J.O., Lacour, J., Bryckaert, M., Tobelem, G. Eur. J. Biochem. (2004) [Pubmed]
  29. Platelet factor 4 (CXC chemokine ligand 4) differentially regulates respiratory burst, survival, and cytokine expression of human monocytes by using distinct signaling pathways. Kasper, B., Brandt, E., Brandau, S., Petersen, F. J. Immunol. (2007) [Pubmed]
  30. RANTES- and interleukin-8-induced responses in normal human eosinophils: effects of priming with interleukin-5. Schweizer, R.C., Welmers, B.A., Raaijmakers, J.A., Zanen, P., Lammers, J.W., Koenderman, L. Blood (1994) [Pubmed]
  31. Regulated expression of platelet factor 4 in human monocytes--role of PARs as a quantitatively important monocyte activation pathway. Schaffner, A., Rhyn, P., Schoedon, G., Schaer, D.J. J. Leukoc. Biol. (2005) [Pubmed]
  32. Cytokines in WBC-reduced apheresis PCs during storage: a comparison of two WBC-reduction methods. Wadhwa, M., Seghatchian, M.J., Dilger, P., Sands, D., Krailadisiri, P., Contreras, M., Thorpe, R. Transfusion (2000) [Pubmed]
  33. beta-Thromboglobulin and platelet-factor 4 in patients with cancer: correlation with the stage of disease and the effect of chemotherapy. Al-Mondhiry, H. Am. J. Hematol. (1983) [Pubmed]
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