Predominant inhibition of interleukin-6 synthesis in patient-specific endothelial cells by mTOR inhibitors below a concentration range where cell proliferation is affected and mitotic arrest takes place.
Organ rejection and inflammation are accompanied by endothelial cell activation. An in vitro model with patient-specific endothelial cells was used to study the impact of mTOR inhibitors on cell growth and release of proinflammatory cytokines.


METHODS
Confluent monolayers of human saphenous vein endothelial cells were pretreated with everolimus or sirolimus followed by induction with tumour necrosis factor-alpha (TNF-alpha).


RESULTS
Incubation with sirolimus or everolimus resulted in a dose-dependent deceleration of cell growth. Compared to control, cell count at high concentrations ceased to increase and remained at 60%. This mitotic arrest was accompanied by a dose-dependent inhibition of the TNF-alpha-induced in situ synthesis and release of interleukin-6 per cell by 60%.


CONCLUSIONS
Under conditions mimicking cytokine-induced cell activation a predominant inhibitory effect of everolimus compared to sirolimus on endothelial cell proliferation was observed paralleled by an inhibition of proinflammatory cytokines. This might attenuate the acute proinflammatory status after transplantation.
Lehle
K
K
Clinic of Cardiothoracic Surgery, University of Regensburg, Regensburg, Germany. karla.lehle@klinik.uni-regensburg.de
Birnbaum
D E
DE
Preuner
J G
JG
D002452:Cell Count; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D001026:Coronary Artery Bypass; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis*; D008938:Mitosis / Q000187:drug effects*; D011494:Protein Kinases / Q000378:metabolism*; D012501:Saphenous Vein; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D000093242:Interleukin-6 Inhibitors
D004791:Enzyme Inhibitors; D000068338:Everolimus; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D011494:Protein Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000093242:Interleukin-6 Inhibitors; C546842:MTOR protein, human