Alternative titles; symbols
HGNC Approved Gene Symbol: PF4
Cytogenetic location: 4q13.3 Genomic coordinates (GRCh38): 4:73,980,811-73,982,124 (from NCBI)
Platelet factor-4 is a 70-amino acid protein that is released from the alpha-granules of activated platelets and binds with high affinity to heparin. Its major physiologic role appears to be neutralization of heparin-like molecules on the endothelial surface of blood vessels, thereby inhibiting local antithrombin III activity and promoting coagulation. As a strong chemoattractant for neutrophils and fibroblasts, PF4 probably has a role in inflammation and wound repair (Eisman et al., 1990).
The full-length PF4 cDNA was prepared by Poncz et al. (1987). Eisman et al. (1990) cloned and sequenced the PF4 gene. Like beta-thromboglobulin (PPBP; 121010), PF4 is encoded by a small inducible gene (SIG), so called because of its small size and its stimulation with platelet activation.
The NOA mouse, an animal model of allergic or atopic dermatitis, exhibits ulcerative skin lesions associated with accumulation of mast cells and eosinophils, a significantly increased level of serum IgE, and scratching behavior. Watanabe et al. (1999) used the differential display technique to screen genes that might be differentially expressed in the spleen of NOA mice as compared to that of controls. They isolated a gene encoding a 105-amino acid protein that has 89% and 64% sequence identity to rat PF4 and human PF4, respectively. Both PF4 and eotaxin (601156), a specific chemoattractant for eosinophils, were expressed more strongly in spleens of adult NOA mice than in younger mice, parallel to the increase in ulcerative skin lesions in older mice. This suggested that PF4 and eotaxin may play important roles in the etiology of atopic dermatitis.
PF4, or CXCL4, belongs to the CXC chemokine family. Chemokines are a group of small (approximately 8-14 kD), mostly basic, structurally related molecules that regulate cell trafficking of various types of leukocytes through interactions with a subset of 7-transmembrane, G protein-coupled receptors. Chemokines also play fundamental roles in the development, homeostasis, and function of the immune system, and they have effects on cells of the central nervous system as well as on endothelial cells involved in angiogenesis or angiostasis. Chemokines are divided into 2 major subfamilies, CXC and CC, based on the arrangement of the first 2 of the 4 conserved cysteine residues; the 2 cysteines are separated by a single amino acid in CXC chemokines and are adjacent in CC chemokines. CXC chemokines are further subdivided into ELR and non-ELR types based on the presence or absence of a glu-leu-arg sequence adjacent and N terminal to the CXC motif (summary by Strieter et al., 1995; Zlotnik and Yoshie, 2000).
Lasagni et al. (2003) identified an isoform of CXCR3 (300574), CXCR3B, as a functional receptor for CXCL4. The found that both CXCR3A and CXCR3B bound CXCL9 (601704), CXCL10 (147310), and CXCL11 (604852), but only CXCR3B bound CXCL4, following expression in a microvascular endothelial cell line. Overexpression of CXCR3A induced an increase in endothelial cell survival, whereas overexpression of CXCR3B upregulated apoptotic pathways. Immunohistochemical analysis of primary microvascular endothelial cells, whose growth in inhibited by CXCL4, CXCL9, CXCL10, and CXCL11, demonstrated expression of CXCR3B, but not CXCR3A. CXCR3B-specific monoclonal antibodies reacted with neoplastic tissue endothelial cells, providing evidence that CXCR3B is expressed in vivo and may account for the angiostatic effects of CXC chemokines, such as CXCL4.
Using mass spectrometry, Aivado et al. (2007) generated serum proteome profiles from 122 patients with myelodysplastic syndrome (MDS), 72 non-MDS patients with cytopenia, and 24 controls, and identified a profile that distinguished MDS from non-MDS cytopenias. Peptide mass fingerprinting and quadrupole SELDI-TOF mass spectrometry identified 2 differential proteins, CXCL4 and CXCL7 (PPBP; 121010), both of which had significantly decreased serum levels in MDS. The decrease was confirmed with independent antibody assays, and subtype analyses revealed decreased serum levels of these 2 proteins in advanced MDS. Aivado et al. (2007) suggested that there may be a concerted disturbance of transcription or translation of these chemokines in advanced MDS.
Using proteome analysis, van Bon et al. (2014) identified increased levels of CXCL4 in skin and plasma plasmacytoid dendritic cells from patients with systemic sclerosis (181750). The study included 779 patients from 5 independent cohorts. The levels of CXCL4 in patients with systemic sclerosis was significantly higher than in controls or compared to patients with systemic lupus erythematosus, ankylosing spondylitis, or liver fibrosis. CXCL4 levels were particularly increased in patients with early diffuse disease. In sclerosis patients, circulating CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro cellular studies showed that CXCL4 downregulated expression of transcription factor FLI1 (193067) and induced secretion of interferon I via toll-like receptors. In mice, infusion of CXCL4 induced the expression of inflammatory markers, promoted the infiltration of inflammatory cells in the skin, and resulted in increased skin thickening. Van Bon et al. (2014) suggested that CXCL4 is a biomarker for fibrosis and pulmonary arterial hypertension in systemic sclerosis, and may be useful in early diagnosis and risk assessment. The findings also implicated a central role for plasmacytoid dendritic cells in the pathogenesis of the disease.
Eisman et al. (1990) demonstrated that the PF4 gene contains 3 exons spanning approximately 1 kb. The gene is encoded on a 10-kb EcoRI fragment of genomic DNA.
By in situ hybridization, Griffin et al. (1987) mapped the PF4 gene to chromosome 4q12-q21. Using PCR of a radiation hybrid panel, Modi and Chen (1998) mapped the PF4 gene to a 1.8-cR interval on 4q. This tight cluster contains many members of the CXC chemokine subfamily, and 2 additional genes, IL8 (146930) and MIG (CXCL9), are located about 6 cR distal to this group. Modi and Chen (1998) suggested that these chemokine genes are all derived through tandem gene duplication from an ancestral gene located on chromosome 4, and that the position of SDF1 (600835) on chromosome 10 represents a translocation event.
By PCR analysis and mapping of YAC clones, O'Donovan et al. (1999) localized a number of CXC chemokine genes to 4q12-q21. They proposed that the order in this region is centromere--IL8--GRO1 (155730)/PPBP/PF4--SCYB5 (600324)/SCYB6 (138965)--GRO2 (139110)/GRO3 (139111)--SCYB11 (CXCL11)--SCYB10 (CXCL10)--MIG--telomere. The PF4 gene was localized to 4q12-q13.
Lambert et al. (2007) found that approximately 8% of 250 healthy individuals had 2-fold increased platelet PF4 content, indicating variable expression in the general population.
In Pf4-null mice and transgenic mice that overexpressed human PF4, Lambert et al. (2007) found an inverse correlation between peripheral blood platelet count and platelet PF4 content. The differences in platelet count appeared to be due to platelet production rather than platelet survival, but the findings were independent of thrombopoietin (THPO; 600044) levels. In vitro studies showed that PF4 inhibited formation of megakaryocyte-containing colonies, and that developing megakaryocytes released PF4 in culture. Anti-PF4 antibodies reduced the duration of thrombocytopenia in mice after chemotherapy.
Aivado, M., Spentzos, D., Germing, U., Alterovitz, G., Meng, X.-Y., Grall, F., Giagounidis, A. A. N., Klement, G., Steidl, U., Otu, H. H., Czibere, A., Prall, W. C., Iking-Konert, C., Shayne, M., Ramoni, M. F., Gattermann, N., Haas, R., Mitsiades, C. S., Fung, E. T., Libermann, T. A. Serum proteome profiling detects myelodysplastic syndromes and identifies CXC chemokine ligands 4 and 7 as markers for advanced disease. Proc. Nat. Acad. Sci. 104: 1307-1312, 2007. [PubMed: 17220270] [Full Text: https://doi.org/10.1073/pnas.0610330104]
Eisman, R., Surrey, S., Ramachandran, B., Schwartz, E., Poncz, M. Structural and functional comparison of the genes for human platelet factor 4 and PF4-alt. Blood 76: 336-344, 1990. [PubMed: 1695112] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0006-4971(20)82480-X]
Griffin, C. A., Emanuel, B. S., LaRocco, P., Schwartz, E., Poncz, M. Human platelet factor 4 gene is mapped to 4q12-q21. Cytogenet. Cell Genet. 45: 67-69, 1987. [PubMed: 3622011] [Full Text: https://doi.org/10.1159/000132431]
Lambert, M. P., Rauova, L., Bailey, M., Sola-Visner, M. C., Kowalska, M. A., Poncz, M. Platelet factor 4 is a negative autocrine in vivo regulator of megakaryopoiesis: clinical and therapeutic implications. Blood 110: 1153-1160, 2007. [PubMed: 17495129] [Full Text: https://doi.org/10.1182/blood-2007-01-067116]
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. A alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as a functional receptor for platelet factor 4. J. Exp. Med. 197: 1537-1549, 2003. [PubMed: 12782716] [Full Text: https://doi.org/10.1084/jem.20021897]
Modi, W. S., Chen, Z.-Q. Localization of the human CXC chemokine subfamily on the long arm of chromosome 4 using radiation hybrids. Genomics 47: 136-139, 1998. [PubMed: 9465307] [Full Text: https://doi.org/10.1006/geno.1997.5100]
O'Donovan, N., Galvin, M., Morgan, J. G. Physical mapping of the CXC chemokine locus on human chromosome 4. Cytogenet. Cell Genet. 84: 39-42, 1999. [PubMed: 10343098] [Full Text: https://doi.org/10.1159/000015209]
Poncz, M., Surrey, S., LaRocco, P., Weiss, M. J., Rappaport, E. F., Conway, T. M., Schwartz, E. Cloning and characterization of platelet factor 4 cDNA derived from a human erythroleukemic cell line. Blood 69: 219-223, 1987. [PubMed: 3098319]
Strieter, R. M., Polverini, P. J., Arenberg, D. A., Kunkel, S. L. The role of CXC chemokines as regulators of angiogenesis. Shock 4: 155-160, 1995. [PubMed: 8574748] [Full Text: https://doi.org/10.1097/00024382-199509000-00001]
van Bon, L., Affandi, A. J., Broen, J., Christmann, R. B., Marijnissen, R. J., Stawski, L., Farina, G. A., Stifano, G., Mathes, A. L., Cossu, M., York, M., Collins, C., and 33 others. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. New Eng. J. Med. 370: 433-443, 2014. [PubMed: 24350901] [Full Text: https://doi.org/10.1056/NEJMoa1114576]
Watanabe, O., Natori, K., Tamari, M., Shiomoto, Y., Kubo, S., Nakamura, Y. Significantly elevated expression of PF4 (platelet factor 4) and eotaxin in the NOA mouse, a model for atopic dermatitis. J. Hum. Genet. 44: 173-176, 1999. [PubMed: 10319581] [Full Text: https://doi.org/10.1007/s100380050136]
Zlotnik, A., Yoshie, O. Chemokines: a new classification system and their role in immunity. Immunity 12: 121-127, 2000. [PubMed: 10714678] [Full Text: https://doi.org/10.1016/s1074-7613(00)80165-x]