Objective IL-17A is implicated in rheumatoid arthritis (RA) pathogenesis; but the contribution of IL-17F remains to be clarified. This report analyses the effects IL-17A versus IL-17F on gene expression, signaling and invasiveness in human RA synoviocytes.
Methods The comparison between IL-17A and F effects on RA synoviocytes was assessed at the mRNA level by microarrays (Affymetrix U133 +2). Western blotting, qRT-PCR, and DNA binding assay were used to evaluate their signaling pathways. The capacities of IL-17A and F alone or in combination with TNF to induce synoviocyte migration and invasion were tested using transwell Matrigel invasion chambers. A functional DNA binding assay was used to evaluate the regulation of Hypoxia Induced Factor 1 (HIF1-α) activation.
Results In microarrays, IL-17A and IL-17F alone had very similar but not identical regulatory effects, IL-17F being less active, with a synergistic pattern in the presence of TNF. This synergistic effect was linked in part to the enhancing expression of TNF RII by IL-17A and F. Regarding their signaling pathway, virtually all IL17A and F inducible genes were dependent on NF-κB activation, whereas a minor number was modulated by p38. Hypoxia-induced pathway was activated by IL-17A and F. Among the hypoxia-induced genes, IL-17A and F alone or combined with TNF induced CXCR4 mRNA (289 fold for IL17A, 34 fold for IL-17F, 450 fold for the combination of IL-17A with TNF). Over expression of CXCR4 at the surface of synoviocytes was confirmed by IF staining. IL-17A and TNF induced in synergy synoviocyte migration and invasion through CXCR4 (6 vs 67 migrated cells/HPF, p≤0.05). Blockade of CXCR4 decreased synoviocyte migration (− 10 fold, p<0.05). The combination of IL-17A or F with TNF induced activation of HIF1-α under normoxic conditions (2 fold, p=0.003).
Conclusion When combined with TNF, IL-17A and F induced very similar but not identical expression pattern in RA synoviocytes, may contribute to the progression of RA through increased synoviocyte aggressiveness. Part of this effect results from a mediated CXCR4/SDF1 pathway. These results are in line with IL-17A and F targeting in RA.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.