Subscribe to RSS
DOI: 10.1055/s-2008-1074548
© Georg Thieme Verlag KG Stuttgart · New York
Hinokitiol, a Natural Tropolone Derivative, Inhibits TNF-α Production in LPS-Activated Macrophages via Suppression of NF-κB
Publication History
Received: January 26, 2008
Revised: April 23, 2008
Accepted: April 27, 2008
Publication Date:
06 June 2008 (online)
Abstract
In this study, we examined the modulatory effect of hinokitiol (HK) on the production of tumor necrosis factor (TNF)-α, a critical factor involved in skin inflammation and hair follicle apoptosis. HK effectively suppressed TNF-α production in lipopolysaccharide (LPS)-activated, macrophage-like (RAW264.7) cells. This compound also diminished mRNA synthesis of TNF-α, indicating that HK-mediated inhibition may occur at the transcriptional level. Moreover, this compound down-regulated the phosphorylation of PDK1, Akt/PKB, and ERK, resulting in a loss of nuclear factor (NF)-κB activation, which is detectable by immunoblotting and reporter gene assays. Therefore, these results suggest that HK may cure hair loss by suppressing factors that promote follicular apoptosis, such as TNF-α, in addition to stimulating new hair growth.
Key words
hinokitiol - TNF-α - NF-κB - macrophages - intracellular signaling cascade
References
- 1 Spatafora M, Gjomarkaj M, Merendino A, Melis M, Chiappara G, Pace E. Antitumour activity of mononuclear phagocytes: role of tumour necrosis factor alpha. Respiration. 1992; 59 (Suppl 1) 47-9
- 2 Takeda K, Akira S. Roles of Toll-like receptors in innate immune responses. Genes Cells. 2001; 6 733-42
- 3 Sekine Y, Yumioka T, Yamamoto T, Muromoto R, Imoto S, Sugiyma K. et al . Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages. J Immunol. 2006; 176 380-9
- 4 Wong M, Ziring D, Korin Y, Desai S, Kim S, Lin J. et al . TNF-alpha blockade in human diseases: Mechanisms and future directions. Clin Immunol. 2008; 126 121-36
- 5 Ruckert R, Lindner G, Bulfone-Paus S, Paus R. High-dose proinflammatory cytokines induce apoptosis of hair bulb keratinocytes in vivo. Br J Dermatol. 2000; 143 1036-9
- 6 Christoph T, Muller-Rover S, Audring H, Tobin D J, Hermes B, Cotsarelis G. et al . The human hair follicle immune system: cellular composition and immune privilege. Br J Dermatol. 2000; 142 862-73
- 7 Tong X, Coulombe P A. Keratin 17 modulates hair follicle cycling in a TNF-alpha-dependent fashion. Genes Dev. 2006; 20 1353-64
- 8 Anderson A B, Gripenberg J. Antibiotic substances from the heart wood of Thuja plicata D. Don; the constitution of beta-thujaplicin. Acta Chem Scand. 1948; 2 644-50
- 9 Ido Y, Muto N, Inada A, Kohroki J, Mano M, Odani T. et al . Induction of apoptosis by hinokitiol, a potent iron chelator, in teratocarcinoma F9 cells is mediated through the activation of caspase-3. Cell Prolif. 1999; 32 63-73
- 10 Kim Y S. A composition for treating alopecia. Korea Patent 0 041 638 2003
- 11 Baba T, Nakano H, Tamai K, Sawamura D, Hanada K, Hashimoto I. et al . Inhibitory effect of beta-thujaplicin on ultraviolet B-induced apoptosis in mouse keratinocytes. J Invest Dermatol. 1998; 110 24-8
- 12 Yokoyama K, Hashiba K, Wakabayashi H, Hashimoto K, Satoh K, Kurihara T. et al . Inhibition of LPS-stimulated NO production in mouse macrophage-like cells by tropolones. Anticancer Res. 2004; 24 3917-22
- 13 Latz E, Visintin A, Lien E, Fitzgerald K A, Monks B G, Kurt-Jones E A. et al . Lipopolysaccharide rapidly traffics to and from the Golgi apparatus with the toll-like receptor 4-MD-2-CD14 complex in a process that is distinct from the initiation of signal transduction. J Biol Chem. 2002; 277 47 834-43
- 14 Cho J Y, Baik K U, Jung J H, Park M H. In vitro anti-inflammatory effects of cynaropicrin, a sesquiterpene lactone, from Saussurea lappa. Eur J Pharmacol. 2000; 398 399-407
- 15 Cho J Y, Fox D A, Horejsi V, Sagawa K, Skubitz K M, Katz D R. et al . The functional interactions between CD98, beta1-integrins, and CD147 in the induction of U937 homotypic aggregation. Blood. 2001; 98 374-82
- 16 Jung K K, Lee H S, Cho J Y, Shin W C, Rhee M H, Kim T G. et al . Inhibitory effect of curcumin on nitric oxide production from lipopolysaccharide-activated primary microglia. Life Sci. 2006; 79 2022-31
- 17 Hardy K, Hunt N H. Effects of a redox-active agent on lymphocyte activation and early gene expression patterns. Free Radic Biol Med. 2004; 37 1550-63
- 18 Nam N H. Naturally occurring NF-kappaB inhibitors. Mini Rev Med Chem. 2006; 6 945-51
- 19 Fishman P, Bar-Yehuda S, Madi L, Rath-Wolfson L, Ochaion A, Cohen S. et al . The PI3K-NF-kappaB signal transduction pathway is involved in mediating the anti-inflammatory effect of IB-MECA in adjuvant-induced arthritis. Arthritis Res Ther. 2006; 8 R33
- 20 Okkenhaug K, Vanhaesebroeck B. New responsibilities for the PI3K regulatory subunit p85 alpha. Sci STKE. 2001; 2001 PE1
- 21 Jiang G, Zhang B B. Pi 3-kinase and its up- and down-stream modulators as potential targets for the treatment of type II diabetes. Front Biosci. 2002; 7 d903-7
- 22 Park J, Hill M M, Hess D, Brazil D P, Hofsteenge J, Hemmings B A. Identification of tyrosine phosphorylation sites on 3-phosphoinositide-dependent protein kinase-1 and their role in regulating kinase activity. J Biol Chem. 2001; 276 37 459-71
Jae Youl Cho, Ph. D.
School of Bioscience and Biotechnology and the Institute of Bioscience and Biotechnology
Kangwon National University
Chuncheon 200–701
Korea
Phone: +82-33-250-6562
Fax: +82-33-253-6560
Email: jaecho@kangwon.ac.kr
Hyeon Yong Lee, Ph. D.
School of Bioscience and Biotechnology and the Institute of Bioscience and Biotechnology
Kangwon National University
Chuncheon 200–701
Korea
Phone: +82-33-250-6455
Fax: +82-33-253-6560
Email: hyeonl@kangwon.ac.kr