Libby's laboratory has described three of the four known tissue inhibitors of MMP found in the atheroma. However, a break in the fibrous cap would not matter but for the ensuing thrombosis. For more than a decade it has been known that macrophages in the core of the human atherosclerotic plaque overexpress tissue factor, a potent procoagulant. But, until recently the molecular switch that turns on tissue factor expression was unknown. The usual soluble cytokines localized in the atheroma do not induce macrophage tissue factor expression.
T cells can induce macrophage tissue factor by contact, but the signal remained elusive.
Recent work from Libby's laboratory likely identifies the missing link between the T cell and the lymphocyte, which are side by side when the human atherosclerotic plaque ruptures. They have studied a new signaling system known as CD 40 ligand, a surface bound signal. The usual soluble cytokines do not induce appreciable tissue factor activity, but recombinant CD 40 ligand and the membranes of activated T cells in a CD-ligand dependent manner briskly induce tissue factor gene expression. The target gene product tissue factor is expressed in the same cell that gives rise to the receptor CD 40 that binds CD 40 ligand. Thus, they believe that CD 40 turns on tissue factor expression during an inflammatory state in the arterial intima.