P099 Comparison of IL-17A and IL-17F effects on different cell types
Authors: M Noack, P MIOSSEC
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Post-doctoral fellow. <h3>Introduction</h3> IL-17A has effects on a growing number of cell types, including synoviocytes, skin fibroblasts or endothelial cells. IL-17A is now a therapeutic target in several inflammatory diseases, including psoriasis, PsA and SPA. IL-17F is the closest member of IL-17A in the IL-17 family and it shares IL-17A biological activities. It is now of interest to target both IL-17A and F. Furthermore, IL-17A and IL-17F can synergize with other cytokines such as TNF or IL-1. <h3>Objectives</h3> The aim of this study is to compare in the same experiments, the effect of IL-17A and IL-17F, in combination or not with TNF and IL-1β, on pro-inflammatory cytokine production (IL-6 and IL-8) first by RA synoviocytes, then extended to other cell types. <h3>Methods</h3> Cells (RA synoviocytes, psoriatic skin fibroblasts, human umbilical vein endothelial cells, myoblasts and hepatocytes) were cultured in presence or not of: IL-17A alone, IL-17F alone, TNF alone, IL-1β alone or combinations, IL-17A/TNF, IL-17A/IL-1β, IL-17A/TNF/IL-1β, IL-17F/TNF, IL-17F/IL-1β IL-17F/TNF/IL-1β. After 48 hour of culture, supernatants were recovered and IL-6 and IL-8 levels were measured by ELISA. A data analysis of microarrays, done on synoviocytes, was realized. <h3>Results</h3> IL-17A and IL-17F alone increased significantly both IL-6 and IL-8 production by synoviocytes, with a higher efficiency for IL-17A. For IL-6, TNF and IL-1β alone had the largest effect on myoblasts, increasing 5 fold the secretion, while for IL-8 it was on skin fibroblasts, increasing at least 5 fold the production. The synergy between IL-17A and TNF was observed on all cells for IL-6 secretion, and for IL-8, only endothelial cells did not show a synergistic effect. For IL-17F and TNF, except endothelial cells, a synergy was also observed, however less powerful than IL-17A/TNF. The effect of the combination IL-17A/IL-1β or IL-17F/IL-1β was more dependent on the cell type, with an additive effect for synoviocytes, and a synergistic effect for hepatocytes. The effect of combination of the three cytokines could induce an additive effect as for synoviocytes or a synergistic effect as for skin fibroblasts. The analysis of microarrays showed 1346 regulated probes, with a measured modulation of more than 2 fold, and 279 probes more than 4 fold, with a stronger effect of IL-17A/TNF combination on cell signalization compared to IL-17F/TNF or each cytokine alone. <h3>Conclusions</h3> IL-17A and IL-17F act in a similar way on the different cell types, by inducing pro-inflammatory cytokine secretion. The difference was the intensity of the response, where IL-17A induced a higher effect than IL-17F. IL-17A and IL-17F activities were potentiated by the combination with TNF and IL-1β. The effect of these combinations on cytokine production was dependent on cell types. These differences may explain different response to treatment according to the primary cell type involved in disease. <h3>Disclosure of Interest</h3> None declared.