Combination of IL-17 and TNFα induces a pro-inflammatory, pro-coagulant and pro-thrombotic phenotype in human endothelial cells
- Department of Clinical Immunology and Rheumatology, Immunogenomics and Inflammation Research Unit, Hopital Edouard Herriot, University of Lyon, Lyon, France
- Correspondence to Professor Pierre Miossec, Department of Clinical Immunology and Rheumatology, Immunogenomics and Inflammation Research Unit, Hopital Edouard Herriot 69437, Lyon, France;
Contributors AH designed the research, analysed data, and wrote the paper. VLN performed the research and analysed data. PM designed the research, analysed data, and wrote the paper.
- Received 20 July 2011
- Accepted 30 November 2011
- Published Online First 18 January 2012
Objective Cardiovascular events remain the leading cause of death in rheumatoid arthritis (RA). To study the role of cytokines in these observations, the effects of tumour necrosis factor α (TNFα) and interleukin (IL)-17, a classical and a new key player in RA, were assessed in endothelial cell (EC) dysfunction.
Methods Primary human EC were treated with IL-17 alone or combined with TNFα. mRNA expression was quantified by qRT PCR and Affymetrix microarrays. The role of IL-17 was studied using functional assays of platelet aggregation, EC migration and invasion.
Results IL-17 alone induced 248 pro-inflammatory genes and 9803, when combined with TNFα. IL-17 plus TNFα induced synergistically chemokine genes such as CCL5, IL-8 and cytokine genes such as IL-6. In contrast, IL-17 decreased genes involved in the regulation of inflammation such as IL-33. IL-17 induced EC migration and invasion in synergy with TNFα. Such invasion was inhibited with an antiCXCR4 antibody, indicating the contribution of the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 axis. Supernatants of IL-17-treated EC induced strong platelet aggregation. IL-17 inhibited endothelial CD39/ATPDase expression, an inhibitor of platelet activation. Finally, IL-17 enhanced genes critical for coagulation such as tissue factor and decreased thrombomodulin, leading to a pro-thrombotic state.
Conclusion These results indicate that IL-17 specifically when combined with TNFα has major pro-coagulant and pro-thrombotic effects on vessels.
Funding This work was supported by the Hospices Civils de Lyon, the Région Rhone-Alpes and a Mérieux research grant. Arnaud Hot was supported by a grant from the French society of internal medicine, SNFMI.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.