516 Non-steroidal anti-inflammatory drugs exacerbate cutaneous Th2 immune response via a prostaglandin E2-EP2 signaling in keratinocytes

Abstract

515 A cosmetic formulation with nitric oxide synthase inhibitors shows improvement in facial erythema G Kalahasti, S Burkes, D Gan, T Florence and M Hines SCR, MaryKay, Dallas, TX Facial Erythema (redness) can be a chronic inflammatory skin condition that is characterized by aberrations in immunological responses and cutaneous vasculature. Pathophysiological changes include elevated expression of cytokines, chemokines, impaired skin barrier function, vasodilation of blood vessels and increased blood flow. Elevated levels of proinflammatory cytokines and Nitric Oxide (NO), a key regulator in vasodilation of blood vessels, have been shown in individuals with persistent redness. Currently, there are very few topical formulations available that effectively improve facial redness. Here, we identified four active materials that significantly reduced the expression of pro-inflammatory cytokines and Nitric Oxide Synthase in cultured normal human epidermal keratinocytes (HEKa) and human umbilical vein endothelial cells (HUVEC). A cosmetic formulation containing these ingredients was clinically tested to evaluate visual improvement of facial redness in vivo. Twenty two subjects with persistent facial erythema applied the cream twice daily over 4 weeks. Evaluations from clinical grading revealed a significant reduction in overall facial redness after 4 weeks. In addition, infrared thermograph image analysis showed a significant reduction in skin temperature compared to baseline that correlated with facial redness. This cosmetic formulation effectively reduced facial erythema with improvements in overall reduction of redness and skin temperature. 516 Non-steroidal anti-inflammatory drugs exacerbate cutaneous Th2 immune response via a prostaglandin E2-EP2 signaling in keratinocytes Y Sawada, T Honda, M Nakamura and K Kabashima 1 Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan and 2 Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used as anti-inflammatory drugs through an inhibition of the activity of cyclooxygenase (COX) and a consequent suppression of prostanoid synthesis. However, topical application of NSAIDs is known to occasionally aggravate Th2-type cutaneous immune responses, such as atopic dermatitis (AD). It raises a concern about the validity of NSAIDs on the treatment of AD. To address this issue, we used a hapten-induced AD mouse model, in which prostaglandin (PG) E2 is abundantly produced in the skin. We found that the mice treated with topical application of NSAIDs exhibited significantly exacerbated AD-like inflammation, an increased number of IL-4 producing Th2 cells in the skin, and an increased serum IgE level. In addition, treatment with NSAIDs enhanced gene expression of thymic stromal lymphopoietin (TSLP) in keratinocytes (KCs) both in vivo and in vitro. Exacerbation of Th2-type skin immune response by NSAIDs was completely abolished in TSLP receptor-deficient mice, indicating that TSLP mediated this exacerbation. We also found that KCs highly expressed EP2, one of PGE2 receptor subtypes, and that the effects of NSAIDs on skin inflammation and TSLP expression in KCs were completely reversed by administration of an EP2 agonist. Moreover, treatment of KCs with an antagonist for EP2 mimicked the effect of NSAID on TSLP expression on KCs. Intriguingly, surface expression of protease-activated receptor 2 (PAR2), which is known to mediate TSLP production by KCs, was down-regulated by EP2 stimulation in a clathrin-dependent manner. These results suggest that PGE2-EP2 signaling plays inhibitory roles for cutaneous Th2-type immune response by down-regulating PAR2 expression on KCs and subsequent TSLP expression.