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 O2−/ROS production and NF-κB-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.
Highlights
Chronic allograft vasculopathy is a pathological condition that impairs endothelial function and integrity and negatively impacts on the half-life of both solid organ engrafted and patients
calcineurin inhibitors (CNIs) induce direct proinflammatory effects in endothelial cells, cultured murine endothelial cells were treated with cyclosporine A (CsA) or tacrolimus under standard in vitro dose and time conditions[10,21] and the mRNA and protein expression of key proinflammatory cytokines and adhesion molecules were assessed by PCR and ELISA assays, respectively
CsA and tacrolimus induced the mRNA synthesis of relevant vascular proinflammatory cytokines and endothelial activation markers, namely IL-6 and TNF-α, and intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), respectively (Fig. 1B)
Summary
Chronic allograft vasculopathy is a pathological condition that impairs endothelial function and integrity and negatively impacts on the half-life of both solid organ engrafted and patients. Recent investigations have highlighted a role of TLR4 in experimental vascular injury by mediating inflammation and dysfunction, remodelling and stiffness associated with spontaneous or induced hypertension in rats[20]. These data pointed to a role of TLR4 activation in vascular damage and dysfunction. We show in this study that in relevant vascular cell types and in aortic tissue, CNIs induce vascular inflammation through a previously non described mechanism involving TLR4 activation
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