title: Combination of IL-17 and TNFα induces a pro-inflammatory, pro-coagulant and pro-thrombotic phenotype in human endothelial cells.
abstract: 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.
  
  
  CONCLUSIONS
  These results indicate that IL-17 specifically when combined with TNFα has major pro-coagulant and pro-thrombotic effects on vessels.
authors.affiliation: Department of Clinical Immunology and Rheumatology, Immunogenomics and Infl ammation Research Unit, Hopital Edouard Herriot, University of Lyon, Lyon, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Hot
authors.forename: Vanina
authors.initials: V
authors.lastname: Lenief
authors.forename: Pierre
authors.initials: P
authors.lastname: Miossec
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics* / Q000378:metabolism; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020381:Interleukin-17 / Q000494:pharmacology*; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D019718:Receptors, CXCR4 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D019138:Antibodies, Blocking; C527276:CXCR4 protein, human; D018925:Chemokines; C506536:IL33 protein, human; D020381:Interleukin-17; D000067596:Interleukin-33; D007378:Interleukins; D019718:Receptors, CXCR4; D014409:Tumor Necrosis Factor-alpha