Abstract 448: Cyclosporine A-Induced Increases in Th17 Cells, Endothelial Dysfunction, and Blood Pressure are Prevented by IL-17 Inhibition Academic Article uri icon

abstract

  • The immunosuppressive drug cyclosporine A (CsA) decreases anti-inflammatory regulatory T cells (Tregs); however its effect on pro-inflammatory Th17 cells and whether IL-17 secreted by Th17 cells plays a role in the development of CsA-induced endothelial dysfunction and hypertension are unknown. We hypothesized that CsA causes endothelial dysfunction and hypertension in part by increasing Th17 cells and these effects can be prevented by IL-17 inhibition. Daily treatment of male C57BL6/J mice for 1 week with CsA (50 mg/kg/day, ip) significantly increased SBP compared to vehicle-treated controls (Con: 993 mmHg vs. CsA: 1383 mmHg; p<0.05) and significantly decreased maximal aortic endothelium-dependent relaxation responses (Con: 693% vs. CsA: 252%; p<0.05). These effects were associated with a significant increase in both splenic and circulating levels of Th17 cells and a significant decrease in both splenic and circulating Tregs. Injections of an IL-17 neutralizing antibody (nAb) on days 0, 3, and 6 of CsA treatment normalized SBP (1089 mmHg) and aortic endothelium-dependent relaxation responses (682%). IL-17 nAb treatment also decreased both splenic and circulating levels of Th17 cells and increased both splenic and circulating levels of Tregs. Injections of an isotype nAb on days 0, 3, and 6 had no effects on SBP in either CsA-treated (1413 mmHg) or vehicle-treated (986 mmHg) mice. The isotype nAb also had no effects on aortic relaxation responses, splenic or circulating levels of Th17 cells, or splenic or circulating levels of Tregs in either CsA-treated or vehicle-treated mice. Together, these data suggest that the hypertension and endothelial dysfunction caused by the immunosuppressive drug CsA is mediated in part by increased Th17 cells and IL-17. Inhibition of IL-17 may have beneficial cardiovascular effects in CsA-treated patients.

published proceedings

  • Hypertension

author list (cited authors)

  • Chiasson, V. L., Chatterjee, P., Young, K. J., Kopriva, S. E., & Mitchell, B. M.

complete list of authors

  • Chiasson, Valorie L||Chatterjee, Piyali||Young, Kristina J||Kopriva, Shelley E||Mitchell, Brett M

publication date

  • September 2012