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

• Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia [11].
• The mean values of the plasma BTG, PF4, and 5-HT concentrations in the migraine group and the MCH group were significantly higher than those in healthy controls [12].
• The plasma levels of beta-Thromboglobulin (beta-TG) and Platelet Factor 4 (PF4) were measured in patients during the normal obstetrical period and in pre-eclampsia [13].
• Platelet count and creatinine were in the normal range in both groups; however, significantly higher levels of beta-TG (P less than 0.0005) and PF4 (P less than 0.0001) were found in case of preeclampsia [14].
• In two out of nine subjects with status asthmaticus, beta-TG or PF4 was elevated, and statistically significant correlations occurred between the initial level of PAF and that of beta-TG or PF4 [15].

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

• As shown by quantitative mRNA analysis, Western blots, radioimmunoprecipitation of cell extracts, and immunofluorescence and quantitatively with enzyme-linked immunosorbent assay, human monocytes express PF4 in the same order of magnitude as the known, regulated CXC chemokine interleukin (IL)-8 [31].
• Prestorage filtration of Spectra LRS PCs did not further reduce the levels of IL-6, IL-8, MCP-1, PF4, beta-TG, and TGF-beta1 in the filtered component [32].
• OBJECTIVE: To evaluate concentrations of the platelet activation markers beta thromboglobulin (BTG) and platelet factor 4 (PF4) in bronchoalveolar lavage fluid (BALF) from patients with systemic sclerosis with and without scleroderma interstitial lung disease (SLD) [3].
• The intravenous administration of various cytotoxic drugs used in cancer chemotherapy produced no immediate measurable changes in BTG and PF4 level [33].
• The supernatant of thrombin-stimulated platelets contained an inhibitor of bFGF-induced mitogenesis; this activity coeluted with PF 4 upon gel filtration, heparin-agarose, and ion-exchange chromatography [10].

References