title: The tumour necrosis factor superfamily ligand APRIL (TNFSF13) is released upon platelet activation and expressed in atherosclerosis.
abstract: Activated platelets release a wide range of inflammatory mediators, including members of the tumour necrosis factor (TNF) superfamily (e.g. CD40 ligand [CD40L] and LIGHT). Such platelet-mediated inflammation could be involved in atherogenesis and plaque destabilisation. In the present study we investigated whether APRIL, another member of the TNF superfamily that has been detected in megakaryocytes, could be released from platelets upon activation. The release of APRIL was studied in thrombin receptor (SFLLRN) activated platelets, and the expression of APRIL was examined in plasma and within the atherosclerotic lesion in patients with carotid and coronary atherosclerosis. Upon SFLLRN activation, there was a gradual release of APRIL, reaching maximum after 90 minutes. While this pattern is similar to that of CD40L and LIGHT, the release of APRIL was quite differently regulated. Thus, prostaglandin E1, but not inhibitors of metal-dependent proteases and actin polymerisation or the lack of GP IIb/IIIa, blocks APRIL release in activated platelets. With relevance to atherogenesis, we found that patients with coronary artery disease (n=80) had raised plasma levels of APRIL as compared with controls (n=20), and APRIL immunoreactivity was detected in aggregated platelets within the ruptured plaque in patients with myocardial infarction and within macrophages in symptomatic carotid plaques. In conclusion, activated platelets release significant amounts of APRIL in a long-lasting manner, differently regulated than the gradual release of other platelet-derived TNF superfamily ligands. The enhanced expression of APRIL in atherosclerotic disorders, both systemically and within the lesion, may suggest a potential involvement of APRIL in atherogenesis.
authors.affiliation: Research Institute for Internal Medicine, Rikshospitalet, Oslo University Hospital, Oslo, Norway.
authors.forename: Wiggo J
authors.initials: WJ
authors.lastname: Sandberg
authors.forename: Kari
authors.initials: K
authors.lastname: Otterdal
authors.forename: Lars
authors.initials: L
authors.lastname: Gullestad
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
authors.forename: Asgrimur
authors.initials: A
authors.lastname: Ragnarsson
authors.forename: Stig S
authors.initials: SS
authors.lastname: Frøland
authors.forename: Jan K
authors.initials: JK
authors.lastname: Damås
authors.forename: Erik
authors.initials: E
authors.lastname: Oie
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.forename: Arne
authors.initials: A
authors.lastname: Yndestad
mesh_terms: D000368:Aged; D000527:Alprostadil / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation; D018179:Receptors, Thrombin / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000276:immunology / Q000378:metabolism
chemical_list: D018179:Receptors, Thrombin; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D023201:CD40 Ligand; D000527:Alprostadil