ИСТИНА

Reverse genetics provides methodology to identify phenotypes associated with particular genetic sequence variations, ex. mutations or a complete gene inactivation. IL6, originally discovered as B cell stimulating factor 2, is the proinflammatory cytokine with pleiotropic functions, ranging from hematopoietic regulation and tissue regeneration to chronic inflammation, autoimmunity and cancer development. Techniques of reverse genetics, such as conditional gene targeting, helped to establish the contributions of IL-6 to various disease states and its physiological functions in healthy organism. Therapeutic inhibitors of IL-6 or of its receptor are already used to treat several autoimmune diseases; however, the systemic inhibition inevitably results in neutralizing the protective functions of this cytokine. Using conditional gene targeting, we are dissecting distinct physiological functions of IL-6 produced by various cell types in the context of the live animal with the idea in mind that pathogenic features in a particular disease may be restricted to only some cellular sources. Similar to other proinflammatory cytokines, IL-6 is elevated in asthma, a common inflammatory disease of the airway, and is playing an active role in this disease. However, the exact molecular mechanism of IL-6 involvement in the pathogenesis of asthma remains largely unknown and the major cellular sources of pathogenic IL-6 havenot been established. To address the role of IL-6 producing cells in allergic airway inflammation, we generated mice with tissue-restricted inactivation of IL-6 in myeloid (Mlys-Cre IL-6fl/fl) and in dendritic (CD11c-Cre IL-6fl/fl) cells and subjected them to intranasal administration of HDM (house dust mite) extract for 5 days per week with additional sensitization treatment for one week prior to the main course. We found that complete genetic inactivation of IL-6 or pharmacological inhibition using blocking antibody ameliorated the disease, with significant decrease in eosinophilia of the lungs. Interestingly, specific deletion of IL-6 in either macrophages or DCs reduced key indicators of allergic inflammation including lymphocyte infiltration, eosinophil and Th2 cell accumulation in the lungs, production of HDM-specific IgE and expression of asthma-associated inflammatory mediators. Taken together, our results indicate that IL-6 plays a pathogenic role in HDM-induced asthma model and that lung macrophages and DCs are the important sources of pathogenic IL-6, thus, providing a rational basis for anti-IL-6 based therapies for patients with asthma. The work was supported by the Russian Science Foundation, grant No. 14-25-00160. Gene expression analysis was supported by the program of fundamental scientific research of the State Academy of Sciences (No 01201363822 ).