ABSTRACT
A critical role of various proteases in skin homeostasis as well as pathobiology, including itch, was described decades ago (Arthur and Shelley 1955; Rajka 1967, 1969; Shelley and Arthur 1955). Later, after the cloning of protease-activated receptors-1 (PAR-1) in 1991 (Vu et al. 1991) and the characterization of PAR-2 in the skin (D’Andrea et al. 1998; Derian et al. 1997; Hou et al. 1998; Santulli et al. 1995; Schechter et al. 1998; Steinhoff et al. 1999), some of the effects of endogenous or exogenous proteases could be attributed-at least in part-to the activation of those G-protein-coupled receptors. In 2000, a role of PAR-2 in skin neurogenic inflammation and later in human pruritus was established (Steinhoff et al. 2000, 2003). This review highlights our current understanding of proteases as histamine-independent pruritogens that are mainly-but not exclusively-mediated via protease-activated receptors. For more detailed information about the cellular mechanisms of PAR function, the reader is referred to exquisitely detailed reviews (Cottrell et al. 2002; Ossovskaya and Bunnett 2004; Steinhoff et al. 2005).
