Calcineurin inhibitors cyclosporine A and tacrolimus induce vascular inflammation and endothelial activation through TLR4 signaling
Open Access
- 13 June 2016
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 6 (1), 27915
- https://doi.org/10.1038/srep27915
Abstract
The introduction of the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus greatly reduced the rate of allograft rejection, although their chronic use is marred by a range of side effects, among them vascular toxicity. In transplant patients, it is proved that innate immunity promotes vascular injury triggered by ischemia-reperfusion damage, atherosclerosis and hypertension. We hypothesized that activation of the innate immunity and inflammation may contribute to CNI toxicity, therefore we investigated whether TLR4 mediates toxic responses of CNIs in the vasculature. Cyclosporine and tacrolimus increased the production of proinflammatory cytokines and endothelial activation markers in cultured murine endothelial and vascular smooth muscle cells as well as in ex vivo cultures of murine aortas. CNI-induced proinflammatory events were prevented by pharmacological inhibition of TLR4. Moreover, CNIs were unable to induce inflammation and endothelial activation in aortas from TLR4(-/-) mice. CNI-induced cytokine and adhesion molecules synthesis in endothelial cells occurred even in the absence of calcineurin, although its expression was required for maximal effect through upregulation of TLR4 signaling. CNI-induced TLR4 activity increased O-2(-)/ROS production and NF-kappa B-regulated synthesis of proinflammatory factors in cultured as well as aortic endothelial and VSMCs. These data provide new insight into the mechanisms associated with CNI vascular inflammation.This publication has 56 references indexed in Scilit:
- A Polymeric Nanomedicine Diminishes Inflammatory Events in Renal Tubular CellsPLOS ONE, 2013
- Endothelial cell transforming growth factor-β receptor activation causes tacrolimus-induced renal arteriolar hyalinosisKidney International, 2012
- Bβ15–42 Attenuates the Effect of Ischemia-Reperfusion Injury in Renal TransplantationJournal of the American Society of Nephrology, 2011
- Klotho Depletion Contributes to Increased Inflammation in Kidney of the db/db Mouse Model of Diabetes via RelA (Serine)536 PhosphorylationDiabetes, 2011
- Toll-like receptor 4 regulates early endothelial activation during ischemic acute kidney injuryKidney International, 2011
- Targeting TLR/IL-1R Signalling in Human DiseasesMediators of Inflammation, 2010
- Proinflammatory phenotype of vascular smooth muscle cells: role of efficient Toll-like receptor 4 signalingAmerican Journal of Physiology-Heart and Circulatory Physiology, 2005
- Intensive Treatment With Atorvastatin Reduces Inflammation in Mononuclear Cells and Human Atherosclerotic Lesions in One MonthStroke, 2005
- Negative regulation of Toll-like receptor-mediated immune responsesNature Reviews Immunology, 2005
- Increased JNK, AP-1 and NF-κB DNA Binding Activities in Isoproterenol-induced Cardiac RemodelingJournal of Molecular and Cellular Cardiology, 1999