Matsuoka Takeshi, Endo Yukina, Kurohane Kohta, Imai Yasuyuki
Laboratory of Microbiology and Immunology, School of Pharmaceutical Sciences, University of Shizuoka.
Biol Pharm Bull. 2018 Dec 1;41(12):1853-1858. doi: 10.1248/bpb.b18-00584. Epub 2018 Oct 2.
Contact hypersensitivity (CHS) to preservatives is receiving increased attention. Parabens are widely used in foods, pharmaceutics and cosmetics as preservatives. The skin sensitizing activity of parabens remains controversial but a few investigations have been made as to whether parabens could facilitate sensitization to other chemicals. We have shown that di-n-butyl phthalate (DBP), a phthalate ester, has an adjuvant effect in a fluorescein isothiocyanate (FITC)-induced CHS mouse model. We have also demonstrated that DBP activates transient receptor potential ankyrin 1 (TRPA1) cation channels expressed on sensory neurons. Comparative studies of phthalate esters revealed that TRPA1 agonistic activity and the adjuvant effect on FITC-CHS coincide. Here we focused on two commonly used parabens, butyl paraben (BP) and ethyl paraben (EP), as to their adjuvant effects. BALB/c mice were epicutneously sensitized with FITC in acetone in the presence or absence of a paraben. Sensitization to FITC was evaluated as the ear-swelling response after FITC challenge. BP but not EP enhanced skin sensitization to FITC, but the effect of BP was much weaker than that of DBP. Mechanistically, BP enhanced the trafficking of FITC-presenting CD11c dendritic cells (DCs) from the skin to draining lymph nodes as well as cytokine production by draining lymph nodes. When the TRPA1 agonistic activity was measured with a cell line expressing TRPA1, BP exhibited higher activity than EP. The present study provides direct in vivo evidence that BP causes sensitization to other chemicals by means of a mouse FITC-CHS model.
对防腐剂的接触性超敏反应（CHS）正受到越来越多的关注。对羟基苯甲酸酯作为防腐剂广泛应用于食品、制药和化妆品中。对羟基苯甲酸酯的皮肤致敏活性仍存在争议，但已有一些关于对羟基苯甲酸酯是否会促进对其他化学物质致敏的研究。我们已经表明，邻苯二甲酸二正丁酯（DBP），一种邻苯二甲酸酯，在异硫氰酸荧光素（FITC）诱导的CHS小鼠模型中具有佐剂作用。我们还证明，DBP可激活感觉神经元上表达的瞬时受体电位锚蛋白1（TRPA1）阳离子通道。邻苯二甲酸酯的比较研究表明，TRPA1激动活性与对FITC-CHS的佐剂作用是一致的。在此，我们聚焦于两种常用的对羟基苯甲酸酯，对羟基苯甲酸丁酯（BP）和对羟基苯甲酸乙酯（EP），研究它们的佐剂作用。在有或没有对羟基苯甲酸酯存在的情况下，用丙酮中的FITC对BALB/c小鼠进行表皮致敏。通过FITC激发后的耳部肿胀反应来评估对FITC的致敏情况。BP而非EP增强了对FITC的皮肤致敏作用，但BP的作用比DBP弱得多。从机制上讲，BP增强了呈递FITC的CD11c树突状细胞（DCs）从皮肤向引流淋巴结的迁移以及引流淋巴结的细胞因子产生。当用表达TRPA1的细胞系测量TRPA1激动活性时，BP表现出比EP更高的活性。本研究通过小鼠FITC-CHS模型提供了直接的体内证据，表明BP可导致对其他化学物质的致敏。
