Increased soluble and platelet-associated CD40 ligand in essential thrombocythemia and reactive thrombocytosis

Viallard, Jean‐François; Solanilla, A.; Gauthier, Bruno; Contin, Cécile; Déchanet, Julie; Grosset, Christophe; Moreau, Jean-François; Perreten, Vincent; Nurden, Paquita; Pellegrin, Jean‐Luc; Nurden, Alan T.; Ripoche, Jean

doi:10.1182/blood.v99.7.2612

Cited by 117 publications

(73 citation statements)

References 12 publications

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“…[37][38][39] CD40L is expressed predominantly by activated T lymphocytes (more frequently in CD4ϩ than in CD8ϩ lymphocytes), but it also is expressed by activated B lymphocytes, NK cells, monocytes, basophils, eosinophils, dendritic cells, and platelets. CD40L also is expressed by nonhematopoietic cells, including endothelial and smooth muscle cells.…”

Section: Cd40 and Cd40l (Cd154)mentioning

confidence: 99%

Clinical implications of the tumor necrosis factor family in benign and malignant hematologic disorders

Younes

Aggarwall

2003

Cancer

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Section: Cd40 and Cd40l (Cd154)mentioning

confidence: 99%

Clinical implications of the tumor necrosis factor family in benign and malignant hematologic disorders

Younes

Aggarwall

2003

Cancer

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“…35 The main reservoir of CD154 in the organism is the blood platelet. 36,37 CD154 expression is inducible by proinflammatory cytokines, and a soluble form (sCD154) retaining biological activity is released from cell surface by a poorly defined mechanism. 38 sCD154 levels are increased in the metabolic syndrome.…”

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confidence: 99%

A protective role for CD154 in hepatic steatosis in mice

et al. 2010

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Inflammation and lipid metabolism pathways are linked, and deregulation of this interface may be critical in hepatic steatosis. The importance of the dialog between inflammatory signaling pathways and the unfolded protein response (UPR) in metabolism has been underlined. Herein, we studied the role of CD154, a key mediator of inflammation, in hepatic steatosis. To this end, Balb/c mice, wild-type or deficient in CD154 (CD154KO), were fed a diet rich in olive oil. In vitro, the effect of CD154 was studied on primary hepatocyte cultures and hepatocyte-derived cell lines. Results showed that CD154KO mice fed a diet rich in olive oil developed hepatic steatosis associated with reduced apolipoprotein B100 (apoB100) expression and decreased secretion of very low-density lipoproteins. This phenotype correlated with an altered UPR as assessed by reduced X-Box binding protein-1 (XBP1) messenger RNA (mRNA) splicing and reduced phosphorylation of eukaryotic initiation factor 2a. Altered UPR signaling in livers of CD154KO mice was confirmed in tunicamycin (TM) challenge experiments. Treatment of primary hepatocyte cultures and hepatocyte-derived cell lines with soluble CD154 increased XBP1 mRNA splicing in cells subjected to either oleic acid (OA) or TM treatment. Moreover, CD154 reduced the inhibition of apoB100 secretion by HepG2 cells grown in the presence of high concentrations of OA, an effect suppressed by XBP1 mRNA silencing and in HepG2 cells expressing a dominant negative form of inositol requiring ER-to-nucleus signaling protein-1. The control of the UPR by CD154 may represent one of the mechanisms involved in the pathophysiology of hepatic steatosis. Conclusion: Our study identifies CD154 as a new mediator of hepatic steatosis. (HEPATOLOGY 2010;52:1968-1979

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“…16 Furthermore, elevated levels of sCD40L are associated with risk of future cardiovascular events in otherwise healthy women. 7 Platelets appear to be an important reservoir of this protein in circulation, because platelet count is correlated with levels of plasma sCD40L 17 : essentially all of the sCD40L generated during the clotting of whole blood is derived from platelets. 13 sCD40L is a bifunctional protein, being involved in both thrombosis and inflammation.…”

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confidence: 99%

Inhibitory Effects of Glycoprotein IIb/IIIa Antagonists and Aspirin on the Release of Soluble CD40 Ligand During Platelet Stimulation

2003

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Background-Glycoprotein (GP) IIb/IIIa antagonists inhibit platelet aggregation, an activity attributed to the clinical benefits of these drugs in settings that involve acute coronary thrombosis. However, platelet activation and subsequent aggregation are now known to cause the release of a soluble form of CD40 ligand (sCD40L), a prothrombotic and proinflammatory protein with GP IIb/IIIa binding activity and an established role in atherosclerotic lesion progression. The present study was designed to determine what effect GP IIb/IIIa antagonists have on the release of sCD40L. Methods and Results-Doses of eptifibatide, abciximab, and tirofiban that inhibited platelet aggregation by at least 80% also inhibited sCD40L release in vitro (by 85%, 57%, and 80%, respectively). When platelets were stimulated with a thrombin receptor agonist, inhibition by GP IIb/IIIa antagonists occurred without affecting the release of ␤TG, an ␣-granule protein. Unexpectedly, concentrations of the 3 antagonists that blocked aggregation by only 20% to 50% potentiated the release of sCD40L (by 19% to 26%). Platelets from aspirin-treated individuals were partially protected from sCD40L release, but only when the agonist was collagen, an affect augmented by the addition of GP IIb/IIIa antagonists. Conclusions-These studies suggest that the mechanisms responsible for the clinical benefits of GP IIb/IIIa antagonists (at doses that optimally inhibit aggregation) and of aspirin may not be limited to the inhibition of thrombosis through their blockade of platelet aggregation but may also involve the inhibition of inflammation and thrombosis through their blockade of sCD40L release. These studies also provide a mechanism by which suboptimal doses of GP IIb/IIIa antagonists may be proinflammatory. . Arterial thrombosis in these settings is dependent on platelet aggregation, a process mediated by the binding of soluble fibrinogen to GP IIb/IIIa on the surface of stimulated platelets. GP IIb/IIIa antagonists are effective in these indications because they block the binding of soluble fibrinogen to GP IIb/IIIa and therefore inhibit platelet aggregation. Interestingly, some trials suggest less accrual of events such as myocardial infarction and death in the treatment arm than are observed in the placebo arm during the year after an event. Thus, the clinical benefit extends well past the time of acute administration of GP IIb/IIIa antagonists, which is often less than 20 hours. 2,3 Although it has been considered that thrombosis-mediated ischemia is a culprit for long-term negative consequences, including atherosclerotic lesion progression after acute arterial coronary thrombosis, it is also possible that thrombosis itself could generate such factors, which could be blocked by GP IIb/IIIa antagonists.Platelet stimulation and subsequent aggregation are known to cause the expression or release of several factors that could affect vascular pathology. These include TXA2, a costimulator of platelets that has vasoconstrictive activity; P-selectin, an ␣-granule...

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Increased soluble and platelet-associated CD40 ligand in essential thrombocythemia and reactive thrombocytosis

Cited by 117 publications

References 12 publications

Clinical implications of the tumor necrosis factor family in benign and malignant hematologic disorders

Clinical implications of the tumor necrosis factor family in benign and malignant hematologic disorders

A protective role for CD154 in hepatic steatosis in mice

Inhibitory Effects of Glycoprotein IIb/IIIa Antagonists and Aspirin on the Release of Soluble CD40 Ligand During Platelet Stimulation

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