ИСТИНА

Inflammation is an important component of the innate immunity. The increased level of pro-inflammatory cytokines, such as TNFa is usually observed in chronic and acute inflammation. The cytokines increase leukocyte adhesion and vascular permeability. One of the key factors mediating intercellular adhesion is ICAM1. Overexpression of ICAM1 is observed under many pathological conditions including autoimmune diseases, vascular dysfunctions and aging. We have previously shown that mitochondria-targeted antioxidant SkQ1 is able to increase the wound healing speed in old animals. In the current work we aimed to elucidate the mechanism underlying SkQ1 activities on endothelium cells, notably ICAM1 expression. Incubation of endothelial cells with picomolar concentrations of SkQ1, or with its derivate without antioxidant moiety C12TPP (C12-triphenilphosphonium), or with classical mitochondrial uncoupler DNP (2, 4-dinitrophenol) led to decreased expression of level of ICAM1 mRNA. These compounds also prevented TNF-a-induced increase in ICAM1 expression as well as secretion of proinflammatory cytokines IL-6 and IL-8. Since SkQ1 and C12TPP were previously shown to have mild uncoupling activity, we assume that mitochondrial uncoupling leads to downregulation of cellular adhesion molecules expression. MAPK- and NF-kB-signaling pathways are the main mechanisms regulating TNFa-related ICAM1 expression. Since MAPK-signaling pathway didn‘t have significant impact on the ICAM1 expression under our experimental conditions we focused on the NF-kB-signaling pathway. We have shown SkQ1 and other uncouplers to inhibit various stages of NF-kB-signaling pathway including IkBa phosphorylation and p65 translocation into the nucleus. In vivo experiments also proved anti-inflammatory activity of SkQ1. The level of ICAM1 mRNA in aortas of SkQ1-treated old mice was significantly lower than the level of ICAM1 mRNA in the aortas of non-treated mice. The obtained results proved that mitochondrial uncouplers downregulate ICAM1 expression via NF-kB-signaling pathway assuming mitochondria to play important role in the inflammatory processes thus opening new possibilities for the development of next generation drugs against various endothelial dysfunctions.