title: Cathepsin E induces itch-related response through the production of endothelin-1 in mice.
abstract: This study investigated the pruritogenic potency of cathepsin E, an aspartic protease, and its mechanisms in mice. An intradermal injection of cathepsin E to the rostral back elicited scratching, an itch-associated response, of the injection site. This action was inhibited by the aspartic protease inhibitor pepstatin A, the endothelin ET(A) receptor antagonist BQ-123, and the opioid receptor antagonists naltrexone and naloxone, but not by the H(1) histamine receptor antagonist terfenadine, the proteinase-activated receptor-2 antagonist FSLLRY-NH(2), or mast cell deficiency. Pepstatin A inhibited scratching induced by intradermal injection of the mast-cell degranulator compound 48/80, but not by tryptase, a mast-cell mediator. An intradermal injection of cathepsin E increased endothelin-1 levels in the skin at the injection site. Preproendothelin-1 mRNA was present in primary cultures of keratinocytes, and immunohistochemistry using an antibody recognizing endothelin-1 and big-endothelin-1 revealed immunoreactivity in the epidermis, especially in the prickle and granular cell layers, but not in the basal cell layer. These results suggest that cathepsin E is an endogenous itch inducer, and that its action is mediated at least in part by the production of endothelin-1 in the epidermis.
authors.affiliation: Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, Japan.
authors.forename: Tsugunobu
authors.initials: T
authors.lastname: Andoh
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yoshida
authors.forename: Jung-Bum
authors.initials: JB
authors.lastname: Lee
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kuraishi
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D020059:Cathepsin E / Q000494:pharmacology*; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D006636:Histamine Release; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010436:Pepstatins / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011537:Pruritus / Q000139:chemically induced / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009292:Narcotic Antagonists; D010436:Pepstatins; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D009270:Naloxone; D009271:Naltrexone; D020059:Cathepsin E; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C031375:pepstatin