Article Text

Download PDFPDF

Pathogenic role of IL-17 in endothelial dysfunction, a link between rheumatoid arthritis and atherosclerosis
  1. A Hot,
  2. V Lenief,
  3. M-A Cazalis,
  4. P Miossec
  1. Research Unit Immunogenomics and Inflammation, Hôpital Edouard Herriot, University of Lyon, Lyon, France

Statistics from

Cardiovascular diseases remain the leading cause of death in rheumatoid arthritis (RA). RA and atherosclerosis share common pathway. Among cytokines involved in RA, interleukin 17 (IL-17) is now seen with a key role. The effect of IL-17 was investigated to better understand its role in endothelial dysfunction, the first step of atherosclerosis.

Primary endothelial cells (EC) were treated with IL-17 (100 ng/ml) alone or combined to tumour necrosis factor (TNF)α (1 ng/ml). mRNA expression was quantified by qRT PCR and by Affymetrix microarrays HG133 A+2. The role of IL-17 was evaluated in EC migration and invasion using a chemoinvasion assay through BM matrigel in modified Boyden chambers. The ability of IL-17 to promote thrombosis through platelet aggregation was assessed using platelet rich plasma incubated with IL-17-treated EC supernatants. Coagulation activation was assessed by the expression of tissue factor.

IL-17 alone induced pro-inflammatory changes in EC, inducing changes of 248 genes. A clear synergistic effect was seen with TNFα and their combination enhanced the expression of 9803 genes. Among the critical genes, IL-17 plus TNFα induced synergistically the expression of chemokine genes such as CCL20 and IL-8 and cytokine genes such as IL-6 and IL-15. In contrast, IL-17 decreased the expression of genes involved in the regulation of inflammation such as IL-4-receptor. Furthermore, IL-17 alone induced the expression of metalloprotease genes such as matrix metalloproteinase 2 (MMP2) and MMP9, known to be involved in atherosclerosis. Using these first results, the effect of IL-17 was tested in a chemo invasion assay through Matrigel to study both cell motility and their ability to cross tissue barriers. IL-17 induced the same level of EC invasion than that induced by TNFα alone. Furthermore, the combination of IL-17 with TNFα resulted in a fivefold increase in invasive activity. Regarding platelet aggregation, IL-17-treated EC supernatants induced a strong platelet aggregation (+61.25%±1.25%), as for TNFα treated EC (58, 5%±1.2%). To better understand the mechanism by which IL-17 promotes platelet aggregation, we evaluated its effect on the inhibitor of platelet activation CD39. IL-17 inhibited the EC CD39/ATPDase expression. Finally, IL-17 was able to enhance the expression of genes critical for coagulation such as tissue factor and plasminogen activator, leading to a thrombotic state.

IL-17 induced a pro-inflammatory phenotype in EC and enhanced their migration, with extracellular matrix destruction. Therapies interfering in the IL-17 pathway may provide not only a new way to treat RA but it may also reduce atherosclerosis.

Request Permissions

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.