THROMBIN MODULATION OF NATURAL-KILLER ACTIVITY IN HUMAN PERIPHERAL LYMPHOCYTES

In addition to its pivotal role in the coagulation cascade, thrombin i s mitogenic for fibroblasts and endothelial cells, and activates a num ber of inflammatory cells including monocytes and T-lymphocytes. To de termine if other immune functions are modulated by thrombin and if thi s modulation is direct or indirect, we investigated whether highly pur ified human alpha-thrombin affects natural killer (NR) and lymphokine- activated killer (LAI) cell-mediated cytotoxicity. Thrombin enhanced N R cell-mediated cytotoxicity by more than 60% and enhanced IL-2 produc tion and NK 3.3 cell responsiveness to IL-2. Unexpectedly, thrombin an d the receptor activating ''tethered ligand'' domain of the thrombin r eceptor (TRP-7:SFLLRNP) inhibited LAK cell-mediated cytotoxicity by 50 %. DIP-thrombin (a proteolytically inactive form of alpha-thrombin) ha d no inhibitory activity, suggesting that proteolytic activation of th rombin receptor is requisite for inhibition. These results indicate th at cell-mediated cytotoxicity may be enhanced by thrombin through a me chanism involving stimulation of cytokine production and NK cell respo nsiveness, but that activation of thrombin receptor may also inhibit c ytotoxic effects of LAK: cells. The role of this dual regulation in pr ocesses of cell surveillance, wound healing, and inflammation remains to be determined. (C) 1996 Academic Press, Inc.