探討SAHA對肥大細胞的調節與在小鼠異位性皮膚炎
動物模式上的影響

異位性皮膚炎是一種反覆且慢性發炎的皮膚疾病。急性時期的病變皮膚中，肥大細胞會被活化並釋出媒介物質，導致 Th2 細胞激素 IL-4、IL-5 及 IL-13 表現量上升；慢性時期則是轉變為大量表現 Th1 細胞激素 IFN-γ。另外 SAHA 是組蛋白去乙醯酶抑制劑家族的一員，先前研究指出 SAHA 可以做為治療表皮性 T 細胞淋巴癌之藥物及具有降低樹突細胞經 LPS 刺激後表現 TNF-α 及 IL-6、IL-12 的功能以及其可誘發調節型 T 細胞的生成，然而 SAHA 對肥大細胞的影響則還不清楚。因此本研究利用肥大細胞指標性細胞株 RBL-2H3 來探討 SAHA 是否具有調控肥大細胞活化的能力，進而達到預防及治療異位性皮膚炎的效果。在細胞實驗的部分，將 RBL-2H3 細胞和不同濃度的 SAHA 共同培養，發現 SAHA 能減少細胞表面分子 FcεRI 的表現量，也能降低 RBL-2H3 細胞刺激後釋出顆粒物質及組織胺的能力，並可減少 TNF-α 和 IL-4 的分泌量。由以上結果顯示 SAHA 能降低 RBL-2H3 細胞的活化程度。接著將 SAHA 應用在預防及治療異位性皮膚炎小鼠動物模式上，實驗結果顯示 SAHA 可以有效的減輕小鼠皮膚發炎的臨床病癥、表皮增厚及肥大細胞浸潤真皮內部的現象，也能抑制經過敏原 OVA 刺激的淋巴結細胞增生程度和 Th2 細胞激素 IL-4、IL-5、IL-10、IL-13 的分泌量；另外能降低全身血清中 OVA 專一性抗體 IgE 和 IgG1 的表現量，並減少經 OVA 刺激的脾臟細胞 IL-4、IL-5、IL-10、IL-13 的分泌量及增生程度，此外也可觀察到 SAHA 能促使表現 Foxp3 之淋巴結細胞的數目增加。由以上實驗結果推測，SAHA 對免疫細胞調控的途徑可能是藉由增加 Foxp3+ 的 T 細胞數目，以達到抑制 Th2 細胞反應的效果，使異位性皮膚炎的症狀獲得改善。因此，SAHA 除了可以做為治療癌症的藥物外，未來或許也能開發成為治療異位性皮膚炎之藥物。

關鍵字

組蛋白去乙醯酶抑制劑；異位性皮膚炎

並列摘要

Atopic dermatitis is a chronic, relapsing inflammatory skin disease. In acute atopic dermatitis skin lesions, activation of mast cells release mediators and up-regulate expression of Th2 cytokines IL-4, IL-5 and IL-13, whereas chronic lesions increase the production of Th1 cytokine IFN-γ. One of histone deacetylase inhibitors, suberoylanilide hydroxamic acid (SAHA), was approved for the treatment of cutaneous T-cell lymphoma and could inhibit TNF-α, IL-6 and IL-12 which produced by LPS-stimulated dendritic cells. Additionally, SAHA induced the generation of foxp3+ regulatory T cells. However, the regulatory role of SAHA on mast cells is unclear. In the present study, we examined the modulatory effects of SAHA on rat RBL-2H3 cells in vitro and also evaluated the preventive and therapeutic effects of SAHA in the animal model of atopic dermatitis. First, the RBL-2H3 cells were treated with different concentrations of SAHA and our data showed that SAHA could down-regulate the surface molecule expression of FcεRI. SAHA also inhibited the DNP-IgE-induced degranulation, the release of histamine and cytokines production of IL-4 and TNF-α from RBL-2H3 cells. These results indicated that SAHA could suppress the activation of RBL-2H3 cells. In prophylactic and therapeutic animal model of atopic dermatitis, treatment with SAHA significantly attenuated the severe levels of skin inflammation, epidermis thickening, infiltration of mast cells in dermis, as well as proliferation and Th2 cytokines secretion in OVA-stimulated lymph-node cells. Additionally, SAHA reduced the expression levels of OVA-specific IgE and IgG1, and decreased the proliferation and production of Th2 cytokines from OVA-stimulated splenocytes. Furthermore SAHA could enhance the population of foxp3+ lymph-node cells. These finding showed that SAHA may improve the symptoms of Th2-dominant atopic dermatitis by increasing the number of Foxp3+ T cells, and provide further evidence for the potential use of SAHA for the treatment of allergic diseases.