Interleukin (IL)-6 is a multifunctional cytokine with a critical role in inflammatory, immunoregulatory and haemopoietic responses. Its receptor consists of an ubiquitously expressed membrane transducing element (gp130) and of the specific element IL-6R-alpha (gp80), present only on hepatocytes and some leukocyte subsets. IL-6R-alpha also exists as soluble protein (sIL-6R) that, in the presence of IL-6, forms a complex able to bind gp130 and, thanks to the mechanism called trans-signaling, transduces IL-6 effect through tyrosine phosphorylation and activation of the signal transducer and transcription activator (STAT)-3. The aim of this study was to analyze the bidirectional relationships between platelet aggregation and IL-6-dependent effects. While platelets do not produce IL-6, we found that resting platelets express gp130, but not gp80, on their membranes. Upon activation by thrombin or calcium ionophore A23187, but not by ADP, the IL-6R-alpha is released in soluble form, while cangrelor, the specific inhibitor of P2Y12 receptor, can partially inhibit sIL-6R release. This sIL-6R is biologically active and, in the presence of IL-6, can trigger IL-6 trans-signaling, inducing an autocrine activation loop (as measured by an increase in gp80 and gp130 content) and STAT3 phosphorylation. On the other hand, IL-6 trans-signaling has no effect on platelet degranulation or aggregation by itself, nor on thrombin-induced platelet aggregation. Our data add an important piece to the puzzle of thrombosis and inflammation: in the presence of IL-6, which can be produced by stressed endothelial cells, the platelet-derived IL-6 trans-signaling could be crucial for the evolution of inflammation within a damaged vessel.

Marino, M., Scuderi, F., Ponte, E., Maiuri, M., De Cristofaro, R., Provenzano, C., Rose John, S., Cittadini, A. R. M., Bartoccioni, E., Novel path to IL-6 trans-signaling through thrombin-induced soluble IL-6 receptor release by platelets, <<JOURNAL OF BIOLOGICAL REGULATORS & HOMEOSTATIC AGENTS>>, 2013; 27 (3): 841-852 [http://hdl.handle.net/10807/52592]

Novel path to IL-6 trans-signaling through thrombin-induced soluble IL-6 receptor release by platelets

Marino, Mariapaola;Scuderi, Flavia;De Cristofaro, Raimondo;Provenzano, Carlo;Cittadini, Achille Renato Maria;Bartoccioni, Emanuela
2013

Abstract

Interleukin (IL)-6 is a multifunctional cytokine with a critical role in inflammatory, immunoregulatory and haemopoietic responses. Its receptor consists of an ubiquitously expressed membrane transducing element (gp130) and of the specific element IL-6R-alpha (gp80), present only on hepatocytes and some leukocyte subsets. IL-6R-alpha also exists as soluble protein (sIL-6R) that, in the presence of IL-6, forms a complex able to bind gp130 and, thanks to the mechanism called trans-signaling, transduces IL-6 effect through tyrosine phosphorylation and activation of the signal transducer and transcription activator (STAT)-3. The aim of this study was to analyze the bidirectional relationships between platelet aggregation and IL-6-dependent effects. While platelets do not produce IL-6, we found that resting platelets express gp130, but not gp80, on their membranes. Upon activation by thrombin or calcium ionophore A23187, but not by ADP, the IL-6R-alpha is released in soluble form, while cangrelor, the specific inhibitor of P2Y12 receptor, can partially inhibit sIL-6R release. This sIL-6R is biologically active and, in the presence of IL-6, can trigger IL-6 trans-signaling, inducing an autocrine activation loop (as measured by an increase in gp80 and gp130 content) and STAT3 phosphorylation. On the other hand, IL-6 trans-signaling has no effect on platelet degranulation or aggregation by itself, nor on thrombin-induced platelet aggregation. Our data add an important piece to the puzzle of thrombosis and inflammation: in the presence of IL-6, which can be produced by stressed endothelial cells, the platelet-derived IL-6 trans-signaling could be crucial for the evolution of inflammation within a damaged vessel.
2013
Inglese
Marino, M., Scuderi, F., Ponte, E., Maiuri, M., De Cristofaro, R., Provenzano, C., Rose John, S., Cittadini, A. R. M., Bartoccioni, E., Novel path to IL-6 trans-signaling through thrombin-induced soluble IL-6 receptor release by platelets, <<JOURNAL OF BIOLOGICAL REGULATORS & HOMEOSTATIC AGENTS>>, 2013; 27 (3): 841-852 [http://hdl.handle.net/10807/52592]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/52592
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