Although 4-1BB (CD137), a member of the tumor necrosis factor (TNF) receptor family, is an inducible T-cell costimulatory molecule, it is also reported to be expressed and involved in activation and proliferation of primary human monocytes. However, its involvement and functions in atherosclerosis are not known yet. We tried to explore the hypothesis that 4-1BB is expressed in human atherosclerotic plaques and is involved in plaque inflammation through monocyte regulations. We examined expression and cellular localization of 4-1BB in human carotid atherosclerotic plaques using specific antibodies. Using THP-1 cells, we investigated the effect of 4-1BB stimulation either alone or in combination with lipopolysaccharide (LPS) on the production of monocytic MMPs and TNF-a. Serum concentration of soluble 4-1BB (s4-1BB) were also measured in CAD patients and compared with age- and sex- matched healthy control subjects. Immunohistochemical analyses of human atherosclerotic plaques revealed expression of 4-1BB which was co-localized with cells carrying CD68, a monocyte/macrophage marker. 4-1BB expression of THP-1 cells was also confirmed by flowcytometric analysis. Stimulation of 4-1BB alone by agonistic antibody (4B4) failed to induce MMP-9 from THP-1 cells, however, concomitant treatment of 4B4 with LPS further increased maximal production of MMP-9 induced by LPS alone. Similar additive effect of 4-1BB ligation on LPS-induced TNF-a was also observed, while 4-1BB ligation alone could not elicit TNF-a production. Serum levels of s4-1BB in patients with unstable agina (10.3- fold increase vs control, p<0.05) and myocardial infarction (8.4-fold increase vs control, p<0.05) were significantly higher than those in patients with stable angina (2-fold increase vs control, p<0.05) or those with healthy subjects (control). 4-1BB is involved in atherosclerosis via decreasing plaque stability through enhancing monocyte-derived TNF-a secretion which acts as an autocrinic agent to induce more induction of extracellular matrix-degrading enzymes. Taken together with the significantly increased serum levels of s4-1BB in patients having rupture-prone plaques, 4-1BB is a useful marker of plaque instability.