CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice.
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.
Olofsson
Peder S
PS
Center for Molecular Medicine, L8:03, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden. Peder.Olofsson@ki.se
Söderström
Leif A
LA
Wågsäter
Dick
D
Sheikine
Yuri
Y
Ocaya
Pauline
P
Lang
François
F
Rabu
Catherine
C
Chen
Lieping
L
Rudling
Mats
M
Aukrust
Pål
P
Hedin
Ulf
U
Paulsson-Berne
Gabrielle
G
Sirsjö
Allan
A
Hansson
Göran K
GK
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*
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