Abstract 220: Interleukin 17 Promotes Endothelial Activation and Neutrophil Recruitment Through Synergistic Action with Tumor Necrosis Factor α
Introduction: Interleukin 17 (IL-17) is the signature cytokine produced by TH17 cells, a novel subset of pro-inflammatory CD4+ T cells. Prior studies have noted elevated serum IL-17 in patients presenting with acute coronary syndrome but little is known regarding the effect of IL-17 on endothelial (EC) activation, a key step in thrombosis and the process of leukocyte and platelet recruitment to sites of inflammation.
Methods and results: We tested the hypothesis that IL-17 would induce a distinct pattern of EC activation and leukocyte recruitment when compared to the TH1 cytokine IFNγ. We found that activation of mouse heart EC with the combination of TNFα and IL-17 but not IFNγ had a synergistic effect on mRNA expression of P-selectin (2.6 fold over TNFα alone, p<0.01) and E-selectin (4.0 fold, p<0.01); as well as the CXCR2-ligands CXCL1 (29.0 fold, p<0.01), CXCL2 (15.2 fold, p<0.01), and CXCL5 (53.4 fold, p<0.05), which are highly chemotactic for neutrophils (PMN). Furthermore, EC activation with TNFα and IL-17 but not IFNγ had a synergistic effect on the level of PMN transmigration (46.9% versus 9.1% for TNFα alone, p<0.01) in a parallel-plate flow chamber model, which was prevented upon perfusion of PMN from CXCR2 (-/-) mice. In addition, TNFα and IL-17 had a synergistic effect on microvascular inflammation in vivo as determined by intravital microscopy of cremasteric leukocyte rolling velocity (8.9 μm/s versus 23.9 μm/s for TNFα alone, p<0.01) and perivascular infiltration (22.4 cells/field versus 13.9 cells/field, p<0.01) at 16hr after cytokine injection. By contrast, treatment with TNFα and IFNγ but not IL-17 induced the expression of ICAM1 (2.0 fold over TNFα alone, p<0.05) and VCAM1 (1.6 fold, p<0.01), as well as the T-cell chemokines, CXCL9 (187.4 fold, p<0.01), CXCL10 (2.9 fold, p<0.01), and CCL5 (2.6 fold, p<0.01). Accordingly, treatment with TNFα and IFNγ but not IL-17 preferentially enhanced the transmigration of effector CD4+ T cells under shear flow (41.9% versus 29% for TNFα alone, p<0.01).
Conclusion: IL-17 and TNFα act in a synergistic manner to induce a pattern of EC activation that favors selective PMN recruitment to sites of inflammation, providing a potential link between IL-17 and risk of atherosclerotic plaque rupture and thrombosis.
- © 2012 by American Heart Association, Inc.