Induction of leukotriene B4 and prostaglandin E2 release from keratinocytes by protease-activated receptor-2-activating peptide in ICR mice

Protease-activated receptor-2 (PAR2) has been shown to play a key role in the pathophysiology of itch. However, the precise mechanism of PAR2-mediated itch remains largely unknown. In the present study, we investigated the effects of several agents on the scratching behavior induced by PAR2-activating peptide (SLIGRL-NH2). Pretreatment of experimental animals with tacrolimus or the 5-lipoxygenase inhibitor zileuton significantly reduced SLIGRL-NH2-induced scratching behavior, whereas histamine H1 receptor antagonist cetirizine or the cyclooxygenase inhibitor indomethacin had little effect. Furthermore, intradermal injection of SLIGRL-NH2 increased cutaneous levels of LTB4 and PGE2. In vitro, SLIGRL-NH2 treatment enhanced LTB4 and PGE2 release from primary keratinocytes in a concentration-dependent manner. Preincubation of keratinocytes with zileuton resulted in a significant decrease of LTB4 release and treatment of indomethacin led to a significant decrease of PGE2 in response to SLIGRL-NH2 stimulation. In addition, SLIGRL-NH2-induced secretion of LTB4 and PGE2 was significantly inhibited by tacrolimus, whereas cetirizine had no effect. These results indicate that SLIGRL-NH2 stimulates LTB4 and PGE2 release from mouse keratinocytes and that enhancement of LTB4 and PGE2 secretion contributes to SLIGRL-NH2-induced scratching behavior in ICR mice.