Impact of Interleukin-6 family cytokine signalling on human endothelial cells and platelets

Abstract: Endothelial cells lining the luminal side of blood vessels creates a barrier between the circulating blood and the extracellular matrix. Endothelial cells have important functions in regulation of vessel tension and inflammation. Furthermore, endothelium-derived vasodilators prevent our smallest blood cells, platelets, to aggregate in the circulation. The main physiological role of platelets is to protect us from bleeding by creating aggregates at sites of injury. Platelets is also increasingly recognised as mediators in acute inflammation. The focus of this thesis has been to study the impact of inflammatory cytokines in the interleukin (IL)-6 family on endothelial cells and platelets. IL-6 has pleiotropic effects where IL-6 trans-signalling via the soluble IL-6 receptor (IL-6R) is associated to more pro-inflammatory outcomes than classic signalling via the membrane bound IL-6R. Both classic and trans-signalling need the ubiquitously expressed glycoprotein (gp)130 to induce intracellular signalling. Since the IL-6R is expressed on a restricted number of cell types, transsignalling exerts a broader IL-6 response. Paper I reveal that endothelial cells express IL-6R which facilitates both classic and trans-signalling. IL-6 trans-signalling activates more signalling pathways and results in proinflammatory responses in contrast to classic signalling. Paper II show that IL-6 trans-signalling, but not classic signalling occurs in platelets and results in inhibition of epinephrine-induced platelet aggregation. Paper III reveal inter-individual differences in platelet reactivity towards activators and the inhibitor nitric oxide (NO). Individuals with more NOsensitive platelets showed greater capacity of vasodilation, indicating a connection between endothelial function and platelet inhibition. In Paper IV, the impact of various gp130 signalling cytokines on endothelial cells revealed differences and similarities in intracellular signalling, gene expression and protein release. In summary, this thesis investigates the impact of the IL-6 family cytokines on endothelial cells and platelets in regards of intracellular signalling and functional responses.