Chemokines are important mediators of cell migration, and thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) are well-known typical inflammatory chemokines involved in atopic dermatitis (AD). (+)-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 a (TNF-alpha)/interferon gamma (IFN-gamma)-induced expression of Th2 chemokines in HaCaT cells. We found that (+)-nootkatone inhibited the TNF-alpha/IFN-gamma-induced expression of TARC/CCL17 and MDC/CCL22 mRNA in HaCaT cells. It also significantly inhibited TNF-alpha/IFN-gamma-induced activation of nuclear factor kappa B (NF-1(B), p38 mitogenactivated protein kinase (MAPK), and protein kinase C (PKCc). Furthermore, we showed that PKq and p38 MAPK contributed to the inhibition of TNF-alpha/IFN-gamma-induced TARC/CCL17 and MDC/CCL22 expression by blocking I kappa B alpha degradation in HaCaT cells. Taken together, these results suggest that (+)-nootkatone may suppress TNF-alpha/IFN-gamma-induced TARC/CCL17 and MDC/CCL22 expression in HaCaT cells by inhibiting of PKC zeta and p38 MAPK signaling pathways that lead to activation of NF-kappa B. We propose that (+)-nootkatone may be a useful therapeutic candidate for inflammatory skin diseases such as AD. (C) 2014 Elsevier Inc. All rights reserved.