(+)-Nootkatone inhibits tumor necrosis factor α/interferon γ-induced production of chemokines in HaCaT cells.
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 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 TARC/CCL17 and MDC/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 Cζ (PKCζ). Furthermore, we showed that PKCζ and p38 MAPK contributed to the inhibition of TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression by blocking IκBα degradation in HaCaT cells. Taken together, these results suggest that (+)-nootkatone may suppress TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression in HaCaT cells by inhibiting of PKCζ 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.
College of Pharmacy, Ajou University, Suwon 443-749, Republic of Korea.
Hyeon-Jae
HJ
Choi
College of Pharmacy, Ajou University, Suwon 443-749, Republic of Korea.
Jin-Hwee
JH
Lee
College of Pharmacy, Ajou University, Suwon 443-749, Republic of Korea; Research Institute of Pharmaceutical Sciences and Technology, Ajou University, Suwon 443-749, Republic of Korea. Electronic address: yisjung@ajou.ac.kr.
Yi-Sook
YS
Jung
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D054414:Chemokine CCL17 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D054422:Chemokine CCL22 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D003876:Dermatitis, Atopic / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D000081223:Polycyclic Sesquiterpenes; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D012717:Sesquiterpenes / Q000494:pharmacology*; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; C106230:CCL17 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D016328:NF-kappa B; D000081223:Polycyclic Sesquiterpenes; D012333:RNA, Messenger; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D011493:Protein Kinase C; C050302:nootkatone
(+)-Nootkatone; Atopic dermatitis; HaCaT cells; MDC/CCL22; TARC/CCL17