A NOVEL BIOLOGIC ACTIVITY OF THROMBIN - STIMULATION OF MONOCYTE CHEMOTACTIC PROTEIN-PRODUCTION

Thrombin is a serine protease that is released at sites of vascular injury and exerts a variety of biologic effects on different cell types. Thrombin is postulated to play a role in the pathogenesis of a number of diseases including atherosclerosis, since it activates vascular smooth muscle and endothelial cells. Thrombin mediates these effects through a specific receptor that is upregulated in vascular cells in atherosclerosis. Atherosclerosis and glomerulosclerosis are characterized by the presence of monocyte-macrophages in the lesions. Monocyte chemotactic protein (MCP-1) is believed to be an important mediator of monocyte recruitment to the tissue and can be induced in a broad variety of cells including mesangial cells. We studied the effect of thrombin on MCP-1 production and gene expression in well-characterized human mesangial cells, vascular pericytes that play a central role in fibrosis of the glomerular microvascular bed. alpha thrombin stimulates MCP-1 production and gene expression in mesangial cells in a dose- and time-dependent manner. Experiments with diisopropylfluorophosphate thrombin and gamma thrombin demonstrate that this thrombin effect requires both receptor binding as well as catalytic activity, features consistent with the known properties of the recently characterized and cloned thrombin receptor. Moreover, a human thrombin receptor activating peptide (TRAP(1-7)) also stimulates MCP-1 production. Northern blot analysis demonstrated that mesangial cells express an mRNA transcript that hybridizes with labeled human thrombin receptor cDNA. These data describe a novel biologic activity of thrombin and suggest an additional mechanism by which this coagulation factor may participate in the progression of glomerulosclerosis, and by analogy, atherosclerosis.