Thrombin modulation of natural killer activity in human peripheral lymphocytes

In addition to its pivotal role in the coagulation cascade, thrombin is mitogenic for fibroblasts and endothelial cells, and activates a number of inflammatory cells including monocytes and T-lymphocytes. To determine if other immune functions are modulated by thrombin and if this modulation is direct or indirect, we investigated whether highly purified human alpha-thrombin affects natural killer (NR) and lymphokine-activated killer (LAI) cell-mediated cytotoxicity. Thrombin enhanced NR cell-mediated cytotoxicity by more than 60% and enhanced IL-2 production and NK 3.3 cell responsiveness to IL-2. Unexpectedly, thrombin and the receptor activating ''tethered ligand'' domain of the thrombin receptor (TRP-7:SFLLRNP) inhibited LAK cell-mediated cytotoxicity by 50%. DIP-thrombin (a proteolytically inactive form of alpha-thrombin) had no inhibitory activity, suggesting that proteolytic activation of thrombin receptor is requisite for inhibition. These results indicate that cell-mediated cytotoxicity may be enhanced by thrombin through a mechanism involving stimulation of cytokine production and NK cell responsiveness, but that activation of thrombin receptor may also inhibit cytotoxic effects of LAK: cells. The role of this dual regulation in processes of cell surveillance, wound healing, and inflammation remains to be determined.