Platelets induce Pai-1 mRNA expression in monocytes through TGF-BETA

Introduction: Plasminogen activator inhibitor type-1 (PAI-1) is a physiological modulator of fibrinolysis. High plasma PAI-1 is associated with the 4G/5G promoter polymorphism and with increased cardiovascular risk. Here we explored the role of platelets in regulating expression of the PAI-1 gene in monocytes. Methods: Blood from PAI-1 4G/5G genotyped volunteers (n=6) was incubated with the platelet GPVI-specific agonist, cross-linked collagen related peptide (CRP-XL), in the presence or absence of Mab 9E1 that blocks the binding of P-selectin to PSGL1. Monocytes were isolated by +ve selection on CD14 beads and monocyte PAI-1 mRNA expression was measured by real-time PCR. Results: Activation of platelets with CRP-XL resulted in platelets binding to >70% of monocytes and was accompanied by >5000-fold induction of PAI-1 mRNA, peaking at 4hrs. PAI-1 expression was independent of the 4G/5G genotype. Blocking the binding of platelets to monocytes enhanced PAI-1 induction (p<0.05 at 4 hrs). Incubation of isolated monocytes with the releasate from CRP-XL stimulated platelets also led to PAI-1 mRNA expression. The platelet secretome contains >100 different proteins. To identify the soluble factor(s) responsible for induction of PAI-1, neutralizing antibodies to likely candidates were added to monocytes incubated with the platelet releasate. Anti- TGF-beta inhibited platelet releasate-mediated PAI-1 mRNA induction by >80%. Monocyte PAI-1 was also induced by stimulation of PSGL-1 with a P-selectin-Fc chimera, in the absence of platelets, which was also blocked by the TGF-beta antibody. Conclusions: These results suggest that platelets induce PAI-1 mRNA in monocytes predominantly via TGF-beta, released from both platelets, and monocytes via activation by PSGL-1 signalling.This stimulation is independent of 4G/5G genotype

Russia and the Arab Spring: supporting the counter-revolution

Russia’s response to the Arab Spring ranged from apprehension to deep anxiety and diverged significantly from the US and the EU responses. While initially welcoming the popular demands for political reform in North Africa, the Russian reaction rapidly became more critical as a result of Western military intervention into Libya and the threat of the spread of Islamist extremism. It was these twin fears which prompted the Russian leadership to adopt an uncompromizing stance towards Syria. While geopolitical factors certainly played a role in driving Russian strategy, domestic political factors were also more significant. As the Russian leadership felt internally threatened by the growing opposition within the country, conflict in the Middle East highlighted the perceived flaws of the imposition of Western liberal democracy and the virtues of Russia’s own model of state-managed political order. There was, as such, a significant ideational and ideological dimension to the Russian response to the Arab Spring.

Assessing the influence of the Responsibility to Protect on the UN Security Council during the Arab Spring

This article challenges those perspectives which assert first, that the Security Council’s engagement with the Responsibility to Protect (R2P) during the Arab Spring evidences a generally positive trend, and second, that the response to the Arab Spring, particularly Syria, highlights the need for veto restraint. With respect to the first point, the evidence presented in this article suggests that the manner in which R2P has been employed by the Security Council during this period evidences three key trends: first, a willingness to invoke R2P only in the context of Pillar I; second, a pronounced lack of consensus surrounding Pillar III; and third, the persistent prioritisation of national interests over humanitarian concerns. With respect to veto restraint, this article argues that there is no evidence that this idea will have any significant impact on decision-making at the Security Council; the Council’s response to the Arab Spring suggests that national interests continue to trump humanitarian need.