Atopic dermatitis (AD) is a inflammatory skin disease associated with allergy and it is commonly characterized with skin dry, severe pruritus, high serum IgE levels and eosinophilia. Keratinocytes produce many chemokines which are involved in the pathogenesis of skin disorders. In particular, thymus and activation-regulated chemokine (TARC/CCL17) & macrophage-derived chemokine (MDC/CCL22) are Th2-type chemokines, and it has been reported that serum TARC and MDC levels are associated with AD disease activity. (+)-Nootkatone is the major component of Cyperus rotundus. (+)-Nootkatone has antiallergic, anti-inflammatory, and antiplatelet activities. The purpose of this study was to investigate the effect of (+)-nootkatone on tumor necrosis factor α (TNF-α)/interferon γ (IFN-γ)-induced expression of Th2 chemokines in HaCaT cells. We found that (+)-nootkatone inhibited the TNF-α/IFN-γ-induced expression of CCL17 and CCL22 mRNA in HaCaT cells. It also significantly inhibited TNF-α/IFN-γ-induced activation of nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase (MAPK), and protein kinase C zeta (PKC ζ). Furthermore, we showed that PKC ζ and p38 MAPK contributed to the inhibition of TNF-α/IFN-γ-induced CCL17 and CCL22 expression by blocking IκBα degradation in HaCaT cells. Taken together, these results suggest that (+)-nootkatone may suppress TNF-α/IFN-γ-induced CCL17 and CCL22 expression in HaCaT cells by inhibiting of PKC ζ and p38 MAPK signaling pathways that lead to activation of NF-κB. We propose that (+)-nootkatone may be a useful therapeutic candidate for inflammatory skin diseases such as AD.
