Cxcl4

Author:Prof. Dr. med. Peter Altmeyer

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Last updated on: 14.04.2024

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Synonym(s)

chemokines (C-X-C motif) ligand 4; C-X-C motif chemokine 4; Iroplact; Oncostatin-A; Platelet factor 4

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General informationThis section has been translated automatically.

Chemokines, a subgroup of cytokines, are small (size between 8 and 10 kDa), chemotactically active proteins (signaling proteins). They are found in all vertebrates, some virus species and bacteria. Around 50 chemokines are currently known in humans. A strongly conserved structural feature of all chemokines is a fixed group of cysteine residues that is stabilized by 1 or 2 disulfide bridges. This key structural position in the molecule is responsible for their fixed 3-dimensional structure (see chemokines below).

In the CC chemokines, the cysteines follow each other directly, in the CXC chemokines they are separated by 1 (see figure), in the CXXXC chemokines by 3 other amino acids. Chemokines are produced and secreted by a large number of immune cells. They transmit their signals by means of specific chemokine receptors via G proteins. Some chemokines have a pro-inflammatory effect, others have a regulatory effect on the development and homeostasis of tissues.

Increased chemokine expression is found in chronic inflammatory diseases such as HIV infection, atopic eczema, bronchial asthma, allergic rhinitis and psoriasis vulgaris. Chemokines play a positive role, for example, in wound healing, hematopoiesis (blood formation) or the defense against infections. The fact that chemokine receptors are not only present on inflammatory cells, but also on tumor cells and endothelial cells, suggests that they are also involved in the migration of tumor cells or the metastatic behavior of various tumors.

CXCL4, also known as "chemokine (C-X-C motif) ligand 4" or platelet factor 4 (PF4), is a small protein from the group of CXC chemokines. CXCL4 binds to a variant of the chemokine receptor CXCR3 (CXCR3B) and to glycosaminoglycans (GAG). The chemokine protein is encoded by the PF4 gene, which is located on chromosome 4q13.3.

OccurrenceThis section has been translated automatically.

CXCL4 is released from the alpha granules of activated platelets and binds with a high affinity to heparin. The main function of CXCL4 is the neutralization of heparin-like substances on the surface of the endothelia of blood vessels. Through this function, CXCL4 inhibits antithrombin III activity during the aggregation phase of platelets and processes coagulation (see also platelet factor 4). Furthermore, CXCL4 inhibits the proliferation and migration of endothelia. The chemokine suppresses angiogenesis. Furthermore, CXCL4 acts as a chemoattractant for neutrophil granulocytes, monocytes and fibroblasts.

CXCL4 aggregates with herparin to a PF4/heparin complex. This complex represents the antigen in type II heparin-induced thrombocytopenia (HIT II - D69.58). In previously sensitized patients, within a few hours after heparin administration, a drop in platelets (>50% of the initial value) occurs, clinically a "white clot syndrome" with the occurrence of life-threatening thromboses. Venous: arterial thrombosis ratio = 5:1, most frequently pulmonary embolism.

In systemic sclerosis (scleroderma) the serum levels of CXCL4 are significantly elevated. In one study, serum levels correlated with the progression and extent of complications such as pulmonary fibrosis of pulmonary arterial hypertension. This chemokine may prove to be a reliable biomarker for this disease.

The CCXCL4/heparin complex (syn: platelet factor 4/heparin complex) is highly regulated in liver cirrhosis.

CXCL4 kills malaria pathogens within erythrocytes by lysing the digestive vacuoles of the parasites.

However, CXCL4L1 also appears to play a role in the pathogenesis of malignant tumors. Thus, a variant of the CXCL4 gene, the CXCL4L1 gene, is highly expressed in primary pancreatic cancer as well as in its metastases. The significance of this finding remains to be seen.

LiteratureThis section has been translated automatically.

  1. Gleissner CA (2012) Platelet-derived chemokines in atherogenesis: what's new? Curr Vasc Pharmacol 10:563-569.
  2. Lasagni L et al (2007) PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion. Blood 109: 4127-4134.
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  4. Struyf S et al (2004) Platelets release CXCL4L1, a nonallelic variant of the chemokine platelet factor-4/CXCL4 and potent inhibitor of angiogenesis. Circ Res 95: 855-857.
  5. Vandercappellen J et al (2011) The role of the CXC chemokines platelet factor-4 (CXCL4/PF-4) and its variant (CXCL4L1/PF-4var) in inflammation, angiogenesis and cancer. Cytokine Growth Factor Rev 22:1-18.
  6. van Bon L et al (2014) Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med 370:433-443.
  7. Volkmann ER et al (2016) Changes in plasma CXCL4 levels are associated with improvements in lung function in patients receiving immunosuppressive therapy for systemic sclerosis-related interstitial lung disease. Arthritis Res Ther 18:305.
  8. Wang Z et al (2013) Platelet factor-4 (CXCL4/PF-4): an angiostatic chemokine for cancer therapy. Cancer Lett 331:147-153.
  9. Zaldivar MM et al (2010) CXC chemokine ligand 4 (Cxcl4) is a platelet-derived mediator of experimental liver fibrosis. Hepatology 51: 1345-1353.

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Last updated on: 14.04.2024