title: Novel path to IL-6 trans-signaling through thrombin-induced soluble IL-6 receptor release by platelets.
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.
authors.affiliation: Institute of General Pathology, Catholic University School of Medicine, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Marino
authors.forename: F
authors.initials: F
authors.lastname: Scuderi
authors.forename: E
authors.initials: E
authors.lastname: Ponte
authors.forename: M T
authors.initials: MT
authors.lastname: Maiuri
authors.forename: R
authors.initials: R
authors.lastname: De Cristofaro
authors.forename: C
authors.initials: C
authors.lastname: Provenzano
authors.forename: S
authors.initials: S
authors.lastname: Rose-John
authors.forename: A
authors.initials: A
authors.lastname: Cittadini
authors.forename: E
authors.initials: E
authors.lastname: Bartoccioni
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D000001:Calcimycin / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D019947:Receptors, Interleukin-6 / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013917:Thrombin / Q000494:pharmacology*
chemical_list: D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000001:Calcimycin; D000244:Adenosine Diphosphate; D013917:Thrombin