Proteinase-Activated Receptors: Transducers of Proteinase-Mediated Signaling in Inflammation and Immune Response

Abstract

Serine proteinases such as thrombin, mast cell tryptase, trypsin, or cathepsin G, for example, are highly active mediators with diverse biological activities. So far, proteinases have been considered to act primarily as degradative enzymes in the extracellular space. However, their biological actions in tissues and cells suggest important roles as a part of the body's hormonal communication system during inflammation and immune response. These effects can be attributed to the activation of a new subfamily of G protein-coupled receptors, termed proteinase-activated receptors (PARs). Four members of the PAR family have been cloned so far. Thus, certain proteinases act as signaling molecules that specifically regulate cells by activating PARs. After stimulation, PARs couple to various G proteins and activate signal transduction pathways resulting in the rapid transcription of genes that are involved in inflammation. For example, PARs are widely expressed by cells involved in immune responses and inflammation, regulate endothelial-leukocyte interactions, and modulate the secretion of inflammatory mediators or neuropeptides. Together, the PAR family necessitates a paradigm shift in thinking about hormone action, to include proteinases as key modulators of biological function. Novel compounds that can modulate PAR function may be potent candidates for the treatment of inflammatory or immune diseases.

Granzyme A and thrombin differentially promote the release of interleukin-8 from alveolar epithelial A549 cells

“…We first analyzed the expression of functional PAR-1 in A549 cells we used. Besides proteases, a synthetic sixamino-acid peptide (TRAP-6) can stimulate PAR-1 (Ramachandran and Hollenberg 2008;Steinhoff et al 2005). A rise in [Ca 2? ]…”

“…A rise in [Ca 2? ] i is an indicative of PAR-1 stimulation (Asokananthan et al 2002;Steinhoff et al 2005). TRAP-6 was found to elicit a rise in [Ca 2? ]…”

“…Some of them are known to be involved in the regulation of innate immune inflammatory responses. For instance, thrombin (a blood coagulation protease) and trypsin (a pancreatic digestive protease) stimulate the production and release of cytokines and chemokines in diverse cell types (Ramachandran and Hollenberg 2008;Steinhoff et al 2005). To date, it has been recognized that the effects of thrombin and trypsin on Y. Yoshikawa Á H. Hirayasu Á S. Tsuzuki (&) Á T. Fushiki Laboratory of Nutrition Chemistry, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan e-mail: tkmone@kais.kyoto-u.ac.jp the production of inflammatory mediators are largely attributed to their ability to activate a unique class of G-protein-coupled receptors, named protease-activated receptors (PARs).…”

“…Each of PARs (PAR-1, PAR-2, PAR-3, and PAR-4) is cleaved by certain proteases at a specific site on the N-terminal extension protruding into the extracellular space. In each of the four PARs, the newly exposed N-terminus itself acts as a tethered ligand to activate the receptor through an intramolecular interaction (Ramachandran and Hollenberg 2008;Steinhoff et al 2005). Indeed, thrombin and trypsin cleave PAR-1/PAR-4 and PAR-2, respectively, thereby triggering intracellular signaling pathways involved in the production of inflammatory mediators (Ramachandran and Hollenberg 2008;Steinhoff et al 2005).…”

“…GrA has been considered as a low-affinity ligand of PAR-1 (Parry et al 1996;Steinhoff et al 2005;Suidan et al 1994). For instance, this protease induced neurite retraction, which was inhibited in the presence of an anti-PAR-1 antibody (Suidan et al 1994).…”