Thrombin: To PAR or Not to PAR, and the regulation of inflammation

Abstract

Thrombin, a key final common pathway coagulation cascade proteinase, can be envisioned as one of the body's main sentries, always on the lookout to be rendered active at sites of injury or other stress inducers, and always ready to generate a variety of signals that trigger the defense responses that comprise the process termed inflammation. Thrombin does this job in a clever way, using mechanisms that range from the generation of fibrin from fibrinogen, to the activation of G-protein-coupled receptors. The novel way that thrombin acts on human platelets, by cleaving and stimulating proteolytically activated receptors (PARs), has defined a new role not only for thrombin but also for proteinases in general, as hormone-like agents. Thus, thrombin can be seen as a prototype for a number of proteinases that can regulate cell function either by unmasking the receptor-activating tethered ligand sequence of PARs or by silencing PARs by removing the tethered ligand, thereby preventing activation by other proteinases such as thrombin. To play its role in inflammation, thrombin acts not only via the PARs but also by other mechanisms, such as the activation of metalloproteinases, the generation of active peptides from fibrin and by using non-catalytic mechanisms to trigger cell signalling. This chapter summarizes the several mechanisms (both PAR and non-PAR-related) that thrombin can use to regulate cell and tissue function, with a particular focus on the inflammatory response.