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 60mJ 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 [ 1 4 C]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 [ 1 4 C]arachidonic acid by decreasing the Ca 2 + -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.