Prevention of UVB-induced photoinflammation and photoaging by a polymethoxy flavonoid, nobiletin, in human keratinocytes in vivo and in vitro

Exposure to ultraviolet B (UVB) irradiation induces acute skin inflammation such as erythema (sunburn) and edema, and prostaglandin (PG)E-2 in the epidermis plays an important role as its prominent mediator. In the present study, we investigated the effect of nobiletin (5,6,7,8,3',4'-hexamethoxy flavone) from Citrus depressa, on the production of PGE(2) in UVB-irradiated human keratinocytes. When keratinocytes were irradiated with 60 mJ of UVB/cm(2), the production and gene expression of cyclooxygenase (COX)-2, but not COX-1, were augmented along with an increase in PGE(2) levels. The augmented COX-2 production was transcriptionally suppressed by nobiletin. In addition, neither the release of [C-14]arachidonic acid from membrane phospholipids nor the gene expression of cytosolic phospholipase A(2) (cPLA(2)) was altered in UVB-irradiated human keratinocytes. However, nobiletin was found to inhibit the release of [C-14]arachidonic acid by decreasing the Ca2+-dependent activity of cPLA(2). Furthermore, topical treatment of nobiletin on the skin of the back prevented the UVB-induced increase of transepidermal water loss and hyperplasia of the epidermis in hairless mice. Therefore, these results suggest that nobiletin inhibits the UVB-induced production of PGE(2) not only by suppressing the expression of COX-2 but also by decreasing the activity of cPLA(2) in human keratinocytes. Furthermore, nobiletin may be useful as a novel sunscreen reagent to be applied for protection against photoinflammation and photoaging. (C) 2004 Elsevier Inc. All rights reserved.