title: Everolimus triggers cytokine release by macrophages: rationale for stents eluting everolimus and a glucocorticoid.
abstract: OBJECTIVE
  Stent-based delivery of the mammalian target of rapamycin (mTOR) inhibitor everolimus is a promising strategy for the treatment of coronary artery disease. We studied potential adverse effects associated with mTOR inhibition.
  
  
  RESULTS
  Macrophages in culture were either treated with everolimus or starved to inhibit mTOR. Everolimus led to inhibition of protein translation, activation of p38 MAPK, and the release of proinflammatory cytokines (eg, IL-6, TNFα) and chemokines (eg, MCP1, Rantes) before induction of autophagic death. These effects were also observed with rapamycin, but not after starvation. Everolimus-induced cytokine release was similar in macrophages lacking the essential autophagy gene Atg7 but was inhibited when macrophages were cotreated with p38 MAPK inhibitor SB202190 or the glucocorticoid clobetasol. Combined stent-based delivery of clobetasol and everolimus in rabbit plaques downregulated TNFα expression as compared with everolimus-treated plaques but did not affect the ability of everolimus to induce macrophage clearance.
  
  
  CONCLUSIONS
  mTOR inhibition by everolimus triggers cytokine release in macrophages through inhibition of protein translation and p38 activation. These findings provide a rationale for combined local treatment of atherosclerotic plaques with everolimus and an anti-inflammatory agent.
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. wim.martinet@ua.ac.be
authors.forename: Wim
authors.initials: W
authors.lastname: Martinet
authors.forename: Stefan
authors.initials: S
authors.lastname: Verheye
authors.forename: Inge
authors.initials: I
authors.lastname: De Meyer
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Timmermans
authors.forename: Dorien M
authors.initials: DM
authors.lastname: Schrijvers
authors.forename: Ilse
authors.initials: I
authors.lastname: Van Brussel
authors.forename: Hidde
authors.initials: H
authors.lastname: Bult
authors.forename: Guido R Y
authors.initials: GR
authors.lastname: De Meyer
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D016207:Cytokines / Q000096:biosynthesis*; D004195:Disease Models, Animal; D054855:Drug-Eluting Stents; D004797:Enzyme-Linked Immunosorbent Assay; D000068338:Everolimus; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D046529:Microscopy, Electron, Transmission; D011474:Prosthesis Design; D011817:Rabbits; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D000068338:Everolimus; D020123:Sirolimus