Abstract
Skin inflammation plays a central role in the pathophysiology and symptoms of diverse chronic skin diseases including atopic dermatitis (AD). In this study, we examined if caffeic acid phenethyl ester (CAPE), a skin-permeable bioactive compound from propolis, was protective against skin inflammation using in vitro cell system and in vivo animal disease models. CAPE suppressed TNF-α-induced NF-κB activation and expression of inflammatory cytokines in human keratinocytes (HaCaT). The potency and efficacy of CAPE were superior to those of a non-phenethyl derivative, caffeic acid. Consistently, topical treatment of CAPE (0.5 %) attenuated 12-O-tetradecanoylphorbol-13-acetate(TPA)-induced skin inflammation on mouse ear as CAPE reduced ear swelling and histologic inflammation scores. CAPE suppressed increased expression of pro-inflammatory molecules such as TNF-α, cyclooxygenase-2 and inducible NO synthase in TPA-stimulated skin. TPA-induced phosphorylation of IκB and ERK was blocked by CAPE suggesting that protective effects of CAPE on skin inflammation is attributed to inhibition of NF-κB activation. Most importantly, in an oxazolone-induced chronic dermatitis model, topical application of CAPE (0.5 and 1 %) was effective in alleviating AD-like symptoms such as increases of trans-epidermal water loss, skin thickening and serum IgE as well as histologic inflammation assessment. Collectively, our results propose CAPE as a promising candidate for a novel topical drug for skin inflammatory diseases.
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Albukhari AA, Gashlan HM, El-Beshbishy HA, Nagy AA, Abdel-Naim AB (2009) Caffeic acid phenethyl ester protects against tamoxifen-induced hepatotoxicity in rats. Food Chem Toxicol 47(7):1689–1695. doi:10.1016/j.fct.2009.04.021
Alomar A, Berth-Jones J, Bos JD, Giannetti A, Reitamo S, Ruzicka T, Stalder JF, Thestrup-Pedersen K, European Working Group on Atopic D (2004) The role of topical calcineurin inhibitors in atopic dermatitis. Br J Dermatol 151(Suppl 70):3–27. doi:10.1111/j.1365-2133.2004.06269.x
Bieber T (2008) Atopic dermatitis. N Engl J Med 358(14):1483–1494. doi:10.1056/NEJMra074081
Chen JH, Ho C-T (1997) Antioxidant activities of caffeic acid and its related hydroxycinnamic acid compounds. J Agric Food Chem 45(7):2374–2378. doi:10.1021/jf970055t
Chung TW, Moon SK, Chang YC, Ko JH, Lee YC, Cho G, Kim SH, Kim JG, Kim CH (2004) Novel and therapeutic effect of caffeic acid and caffeic acid phenyl ester on hepatocarcinoma cells: complete regression of hepatoma growth and metastasis by dual mechanism. FASEB J 18(14):1670–1681. doi:10.1096/fj.04-2126com
da Cunha FM, Duma D, Assreuy J, Buzzi FC, Niero R, Campos MM, Calixto JB (2004) Caffeic acid derivatives: in vitro and in vivo anti-inflammatory properties. Free Radic Res 38(11):1241–1253. doi:10.1080/10715760400016139
Frenkel K, Wei H, Bhimani R, Ye J, Zadunaisky JA, Huang MT, Ferraro T, Conney AH, Grunberger D (1993) Inhibition of tumor promoter-mediated processes in mouse skin and bovine lens by caffeic acid phenethyl ester. Cancer Res 53(6):1255–1261
Huang MT, Ma W, Yen P, Xie JG, Han J, Frenkel K, Grunberger D, Conney AH (1996) Inhibitory effects of caffeic acid phenethyl ester (CAPE) on 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion in mouse skin and the synthesis of DNA, RNA and protein in HeLa cells. Carcinogenesis 17(4):761–765
Jung WK, Choi I, Lee DY, Yea SS, Choi YH, Kim MM, Park SG, Seo SK, Lee SW, Lee CM, Park YM, Choi IW (2008) Caffeic acid phenethyl ester protects mice from lethal endotoxin shock and inhibits lipopolysaccharide-induced cyclooxygenase-2 and inducible nitric oxide synthase expression in RAW 264.7 macrophages via the p38/ERK and NF-kappaB pathways. Int J Biochem Cell Biol 40(11):2572–2582
Kart A, Cigremis Y, Ozen H, Dogan O (2009) Caffeic acid phenethyl ester prevents ovary ischemia/reperfusion injury in rabbits. Food Chem Toxicol 47(8):1980–1984. doi:10.1016/j.fct.2009.05.012
Khan AQ, Khan R, Qamar W, Lateef A, Ali F, Tahir M, Muneeb UR, Sultana S (2012) Caffeic acid attenuates 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced NF-kappaB and COX-2 expression in mouse skin: abrogation of oxidative stress, inflammatory responses and proinflammatory cytokine production. Food Chem Toxicol 50(2):175–183. doi:10.1016/j.fct.2011.10.043
Kim SY, Koo JE, Seo YJ, Tyagi N, Jeong E, Choi J, Lim KM, Park ZY, Lee JY (2013) Suppression of Toll-like receptor 4 activation by caffeic acid phenethyl ester is mediated by interference of LPS binding to MD2. Br J Pharmacol 168(8):1933–1945. doi:10.1111/bph.12091
Kumari S, Herzberg B, Pofahl R, Krieg T, Haase I (2014) Epidermal RelA Specifically Restricts Contact Allergen-Induced Inflammation and Apoptosis in Skin. J Invest Dermatol. doi:10.1038/jid.2014.193
Lee JH, Jung KM, Bae IH, Cho S, Seo DB, Lee SJ, Park YH, Lim KM (2009) Anti-inflammatory and barrier protecting effect of Lithospermum erythrorhizon extracts in chronic oxazolone-induced murine atopic dermatitis. J Dermatol Sci 56(1):64–66. doi:10.1016/j.jdermsci.2009.07.001
Lee Y, Shin DH, Kim JH, Hong S, Choi D, Kim YJ, Kwak MK, Jung Y (2010) Caffeic acid phenethyl ester-mediated Nrf2 activation and IκB kinase inhibition are involved in NFκB inhibitory effect: structural analysis for NFκB inhibition. Eur J Pharmacol 643(1):21–28. doi:10.1016/j.ejphar.2010.06.016
Man MQ, Hatano Y, Lee SH, Man M, Chang S, Feingold KR, Leung DY, Holleran W, Uchida Y, Elias PM (2008) Characterization of a hapten-induced, murine model with multiple features of atopic dermatitis: structural, immunologic, and biochemical changes following single versus multiple oxazolone challenges. J Invest Dermatol 128(1):79–86. doi:10.1038/sj.jid.5701011
Michaluart P, Masferrer JL, Carothers AM, Subbaramaiah K, Zweifel BS, Koboldt C, Mestre JR, Grunberger D, Sacks PG, Tanabe T, Dannenberg AJ (1999) Inhibitory effects of caffeic acid phenethyl ester on the activity and expression of cyclooxygenase-2 in human oral epithelial cells and in a rat model of inflammation. Cancer Res 59(10):2347–2352
Murtaza G, Karim S, Akram MR, Khan SA, Azhar S, Mumtaz A, Bin Asad MH (2014) Caffeic acid phenethyl ester and therapeutic potentials. Biomed Res Int 2014:145342. doi:10.1155/2014/145342
Natarajan K, Singh S, Burke TR Jr, Grunberger D, Aggarwal BB (1996) Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proc Natl Acad Sci USA 93(17):9090–9095
Nestle FO, Di Meglio P, Qin JZ, Nickoloff BJ (2009) Skin immune sentinels in health and disease. Nat Rev Immunol 9(10):679–691. doi:10.1038/nri2622
Pasparakis M, Courtois G, Hafner M, Schmidt-Supprian M, Nenci A, Toksoy A, Krampert M, Goebeler M, Gillitzer R, Israel A, Krieg T, Rajewsky K, Haase I (2002) TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417(6891):861–866. doi:10.1038/nature00820
Pramanik KC, Kudugunti SK, Fofaria NM, Moridani MY, Srivastava SK (2013) Caffeic acid phenethyl ester suppresses melanoma tumor growth by inhibiting PI3K/AKT/XIAP pathway. Carcinogenesis 34(9):2061–2070. doi:10.1093/carcin/bgt154
Rao TS, Currie JL, Shaffer AF, Isakson PC (1993) Comparative evaluation of arachidonic acid (AA)- and tetradecanoylphorbol acetate (TPA)-induced dermal inflammation. Inflammation 17(6):723–741
Sud’ina GF, Mirzoeva OK, Pushkareva MA, Korshunova GA, Sumbatyan NV, Varfolomeev SD (1993) Caffeic acid phenethyl ester as a lipoxygenase inhibitor with antioxidant properties. FEBS Lett 329(1–2):21–24
Tian B, Nowak DE, Jamaluddin M, Wang S, Brasier AR (2005) Identification of direct genomic targets downstream of the nuclear factor-kappaB transcription factor mediating tumor necrosis factor signaling. J Biol Chem 280(17):17435–17448. doi:10.1074/jbc.M500437200
Velazquez C, Navarro M, Acosta A, Angulo A, Dominguez Z, Robles R, Robles-Zepeda R, Lugo E, Goycoolea FM, Velazquez EF, Astiazaran H, Hernandez J (2007) Antibacterial and free-radical scavenging activities of Sonoran propolis. J Appl Microbiol 103(5):1747–1756. doi:10.1111/j.1365-2672.2007.03409.x
Wullaert A, Bonnet MC, Pasparakis M (2011) NF-kappaB in the regulation of epithelial homeostasis and inflammation. Cell Res 21(1):146–158. doi:10.1038/cr.2010.175
Zhang M, Zhou J, Wang L, Li B, Guo J, Guan X, Han Q, Zhang H (2014) Caffeic acid reduces cutaneous tumor necrosis factor alpha (TNF-α), IL-6 and IL-1β levels and ameliorates skin edema in acute and chronic model of cutaneous inflammation in mice. Biol Pharm Bull 37(3):347–354
Zilius M, Ramanauskiene K, Briedis V (2013) Release of propolis phenolic acids from semisolid formulations and their penetration into the human skin in vitro. Evid Based Complement Alternat Med 2013:958717. doi:10.1155/2013/958717
Acknowledgments
KM-Lim designed and JE-Koo, ES-Kim, ON-Bae performed experiments. SJ-Bae analyzed the data. KM-Lim and JY-Lee wrote the manuscript. Authors thank Chae-Wook Lee for technical support for experiments. This study was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korean government (MEST) (NRF-2012R1A1A3004541), and the Research Fund, 2013 of the Catholic University of Korea.
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Lim, KM., Bae, S., Koo, J.E. et al. Suppression of skin inflammation in keratinocytes and acute/chronic disease models by caffeic acid phenethyl ester. Arch Dermatol Res 307, 219–227 (2015). https://doi.org/10.1007/s00403-014-1529-8
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DOI: https://doi.org/10.1007/s00403-014-1529-8