CD137 (4-1BB) deficiency reduces atherosclerosis in hyperlipidemic mice.
BACKGROUND
The tumor necrosis factor receptor superfamily, which includes CD40, LIGHT, and OX40, plays important roles in atherosclerosis. CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in human atherosclerotic lesions. However, limited information is available on the precise role of CD137 in atherosclerosis and the effects of blocking CD137/CD137 ligand signaling on lesion formation.


RESULTS
We generated CD137-deficient apolipoprotein E-knockout mice (ApoE(-/-) CD137(-/-)) and LDL-receptor-knockout mice (Ldlr(-/-)CD137(-/-)) to investigate the role of CD137 in atherogenesis. The deficiency of CD137 induced a reduction in atherosclerotic plaque lesions in both atherosclerosis mouse models, which was attributed to the downregulation of cytokines such as interferon-gamma, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha. CD137 signaling promoted the production of inflammatory molecules, including monocyte chemoattractant protein-1, interleukin-6, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, in endothelial cells. Stimulation of CD137 ligand signaling activated monocytes/macrophages and augmented the production of proinflammatory cytokines in atherosclerotic vessels.


CONCLUSIONS
CD137/CD137 ligand signaling plays multiple roles in the progression of atherosclerosis, and thus, blockade of this pathway is a promising therapeutic target for the disease.
Jeon
Hyung Jun
HJ
Division of Life and Pharmaceutical Science, Ewha Womans University, Seoul, Korea.
Choi
Jae-Hoon
JH
Jung
In-Hyuk
IH
Park
Jong-Gil
JG
Lee
Mi-Ran
MR
Lee
Mi-Ni
MN
Kim
Bora
B
Yoo
Ji-Young
JY
Jeong
Se-Jin
SJ
Kim
Dae-Yong
DY
Park
Jeong Euy
JE
Park
Hyun-Young
HY
Kwack
KyuBum
K
Choi
Beom Kyu
BK
Kwon
Byoung S
BS
Oh
Goo Taeg
GT
D053330:4-1BB Ligand / Q000502:physiology*; D000818:Animals; D020296:Animals, Congenic; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D025461:Feedback, Physiological; D005260:Female; D006937:Hypercholesterolemia / Q000150:complications* / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation; D008262:Macrophage Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D053330:4-1BB Ligand; D001057:Apolipoproteins E; D016207:Cytokines; D018836:Inflammation Mediators; D011973:Receptors, LDL; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D007371:Interferon-gamma