Synthetic small interfering RNAs selectively suppress the expression of proinflammatory cytokine genes (IL-25 and TSLP) in experiments in vitro

Abstract

Allergic rhinitis (AR) is an inflammatory disease of the upper respiratory tract (nasal mucosa). AR affects up to 40% of the world’s population; in the Russian Federation, the incidence is 18% to 30%, depending on the region. Despite the fact that AR is not a severe pathology, it causes significant economic burden. Another threat associated with this disease is that in 40% of cases, patients with AR eventually develop a more severe disabling pathology – AD. Widespread prevalence and significant economic disadvantages caused by AR determine the importance of developing new ways of prevention and control of this disease, as the existing methods of therapy are insufficient. However, the search for new ways of therapy is impossible without a detailed investigation of the molecular mechanisms of AR pathogenesis. For a long time it was considered that this allergic inflammation is formed by Th2-dependent mechanism with involvement of Th2-lymphocytes, B-cells and eosinophils and pro-inflammatory cytokines: IL-4, IL-5 and IL-13. However, experimental evidence has now accumulated on the role of epithelial cells of the respiratory tract and the proinflammatory cytokines they secrete (IL-25, IL-33 and TSLP) in the pathogenesis of AR and AD. IL-25 has been shown to induce the production of IL-4, IL-5 and IL-13, directing a Th2-type immune response. At the same time, mice with inactivated IL-25 developed barely any Th2-immune response. Inactivation of IL-33 significantly reduces inflammation (mediated by eosinophils) of the respiratory tract. Mice knockout for the cytokine receptor TSLP did not develop nasal hyperreactivity in response to allergen, but the level of nasal mucosal inflammation remained high. Currently, work is actively progressing on the development of new drugs capable of specifically blocking the activity of the listed cytokines; first of all, drugs based on neutralizing monoclonal antibodies. However, there are other technologies that can be used to regulate the activity of genes, such as the technology based on the RNA interference. It can be used to suppress the expression of any gene with a known nucleotide sequence, including genes encoding pro-inflammatory cytokines.Considering the above, the aim of this work was to design synthetic miRNA molecules and study their ability to specifically block the expression of genes encoding proinflammatory cytokines IL-25 and TSLP in experiments in vitro.