title: CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice.
abstract: BACKGROUND
  Atherosclerosis is a multifactorial disease in which inflammatory processes play an important role. Inflammation underlies lesion evolution at all stages, from establishment to plaque rupture and thrombosis. Costimulatory molecules of the tumor necrosis factor superfamily such as CD40/CD40L and OX40/OX40L have been implicated in atherosclerosis.
  
  
  RESULTS
  This study shows that the tumor necrosis factor superfamily members CD137 and CD137 ligand (CD137L), which play a major role in several autoimmune diseases, may constitute a pathogenic pair in atherogenesis. We detected CD137 protein in human atherosclerotic lesions not only on T cells but also on endothelial cells and showed that CD137 in cultured endothelial cells and smooth muscle cells was induced by proinflammatory cytokines implicated in atherosclerosis. Activation of CD137 by CD137L induced adhesion molecule expression on endothelial cells and reduced smooth muscle cell proliferation. In addition, treatment of atherosclerosis-prone apolipoprotein E-deficient mice with a CD137 agonist caused increased inflammation. T-cell infiltration, mainly of CD8(+) cells, and expression of the murine major histocompatibility complex class II molecule I-A(b) increased significantly in atherosclerotic lesions, as did the aortic expression of proinflammatory cytokines.
  
  
  CONCLUSIONS
  Taken together, these observations suggest that CD137-CD137L interactions in the vasculature may contribute to the progression of atherosclerosis via augmented leukocyte recruitment, increased inflammation, and development of a more disease-prone phenotype.
authors.affiliation: Center for Molecular Medicine, L8:03, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden. Peder.Olofsson@ki.se
authors.forename: Peder S
authors.initials: PS
authors.lastname: Olofsson
authors.forename: Leif A
authors.initials: LA
authors.lastname: Söderström
authors.forename: Dick
authors.initials: D
authors.lastname: Wågsäter
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sheikine
authors.forename: Pauline
authors.initials: P
authors.lastname: Ocaya
authors.forename: François
authors.initials: F
authors.lastname: Lang
authors.forename: Catherine
authors.initials: C
authors.lastname: Rabu
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Mats
authors.initials: M
authors.lastname: Rudling
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Ulf
authors.initials: U
authors.lastname: Hedin
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Paulsson-Berne
authors.forename: Allan
authors.initials: A
authors.lastname: Sirsjö
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
mesh_terms: D053330:4-1BB Ligand / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D002339:Carotid Arteries / Q000166:cytology / Q000502:physiology; D002478:Cells, Cultured; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000378:metabolism; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D012077:Renal Artery / Q000166:cytology / Q000502:physiology; D018709:Statistics, Nonparametric; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000819:agonists / Q000378:metabolism / Q000502:physiology*
chemical_list: D053330:4-1BB Ligand; D001057:Apolipoproteins E; D000949:Histocompatibility Antigens Class II; C474482:I-A(b) antigen, mouse; D012333:RNA, Messenger; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9