title: 15-deoxy-?(12,14)-prostaglandin J2 as a potential TRPV1-dependent atopic dermatitis enhancer.
abstract: Atopic dermatitis (AD) is a recurrent chronic inflammatory skin condition characterized by a complex pathogenesis, including skin barrier dysfunctions, allergy/immunology, and pruritus.In AD lesions, mast cells migrate into the epidermis, and exert their biological effects by releasing paracrine mediators. TRPV1, a non-selective cation channel widely expressed in skin tissues, has been shown to contribute to the development of diverse dermatoses and pruritus. In the present study, we identified a TRPV1 agonist as a neuritogenic enhancer produced from mast cells and characterized a possible molecular mechanism for the TRPV1-dependent neuritogenesis in AD. Based on the hypothesis that activated mast cells produce a TRPV1-dependent neuritogenic enhancer,we screened a number of inflammatory mediators for the neuritogenic-promoting activityand identified a PGD2 metabolite, 15-deoxy-?(12,14)-prostaglandin J2 (15d-PGJ2), as a potential neuritogenic enhancer derived from mast cells. 15d-PGJ2 significantly enhanced the nerve growth factor (NGF)-induced neuritogenesis in PC12 cells, and its enhancing potency was attributed to the electrophilic center of 15d-PGJ2. 15d-PGJ2 indeed activated TRPV1, leading to a significant increase in the intracellular Ca(2) level. In addition, the treatment of PC12 cells with biotinylated 15d-PGJ2 resulted in the formation of a 15d-PGJ2-TRPV1 adduct, indicating that 15d-PGJ2 directly modified the TRPV1 in the cells. Furthermore, 15d-PGJ2 facilitated the NGF-dependent signal transductions including ERK and JNK pathways in a Ca(2 ?)-dependent manner. These findings suggest that 15d-PGJ2 enhances NGF signaling via TRPV1-dependent Ca(2) influx, thereby acting as a potential neuritogenic enhancer in AD.
authors.affiliation: Nagoya University (Graduate School of Bioagricultural Sciences), Division of Biofunctional Chemistry, Japan;. Electronic address: shibatat@agr.nagoya-u.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Nagoya University (Graduate School of Bioagricultural Sciences), Division of Biofunctional Chemistry, Japan;
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Nagoya University (Graduate School of Bioagricultural Sciences), Division of Biofunctional Chemistry, Japan;
authors.forename: Yui
authors.initials: Y
authors.lastname: Matsubara
authors.affiliation: Kyoto University (Graduate School of Engineering), Department of Synthetic Chemistry and Biological Chemistry, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Kyoto University (Graduate School of Engineering), Department of Synthetic Chemistry and Biological Chemistry, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Nagoya University (Graduate School of Bioagricultural Sciences), Division of Biofunctional Chemistry, Japan;
authors.forename: Koji
authors.initials: K
authors.lastname: Uchida