Interleukin-6 Signaling Pathways in Human Vascular Endothelial Cells : Molecular Mechanisms and Associations to Atherosclerosis

Abstract: Interleukin-6 is pleotropic cytokine produced by several types of cells including endothelial cells (ECs). IL-6 acts on target cells via two major signaling mechanisms known as classic signaling and trans-signaling. Whileactivation of IL-6 classic signaling is associated with homeostatic and tissue regeneration functions, the trans-signaling is linked to pro-inflammatory effects. Our studies reveal that ECs respond to both IL-6 classic- aswell as trans-singling pathways in distinct but also overlapping manner.While IL-6 classic-signaling activated JAK/STAT3 pathway, the trans-signaling additionally engaged PI3K/AKT and MAPK/ERK pathways. Further, IL-6 trans-singling, but not classic signaling, led to secretion of proinflammatory chemokine MCP-1 mainly via JAK/STAT3 and PI3K/AKTpathways. In addition, IL-6 trans-signaling regulate expression of angiogenesis related genes to subsequently impair endothelial tube formationability. Autocrine IL-6 classic-signaling, however, was vital to maintainthe angiogenic response of ECs. Further proteomic analyses showed thatIL-6 trans-signaling in ECs regulates secretion of several inflammatoryproteins and also shifts laminin secretion from LAMA4 to LAMA5, whichmight collectively favor binding and trans-endothelial migration of mononuclear cells. In human atherosclerotic plaques, we found that expression of LAMA4 and LAMA5 is altered compared to healthy vessels, andthat the alteration appears to be associated with immune cell content andstability of the plaque. Using plasma IL-6 binary complex, a novel biomarker, we showed a strong association between IL-6 trans-signalingand risk of future myocardial infarction (MI). In addition, we showed thatelevated plasma IL-6 binary complex mediates the association betweentraditional risk factors (hypertension and smoking) and MI, suggestingthat elevated plasma IL-6 binary complex concentration could partly explain the increased risk of MI in smokers and hypertensive participants.

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