Preliminary evidence for involvement of the tumour suppressor gene CHD5 in a family with cutaneous melanoma
Preliminary evidence for involvement of the tumour suppressor gene CHD5 in a family with cutaneous melanoma
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DOI：
10.1111/j.1365-2133.2011.10223.x
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发表时间：
2011-05-01
影响因子：
10.3
通讯作者：
MacKie, R.
中科院分区：
文献类型：
--
作者：
Lang, J.;Tobias, E. S.;MacKie, R.
背景局部应用钙调磷酸酶抑制剂已被证明是治疗特应性皮炎的有效药物.当全身给药时，这些药物通过抑制淋巴细胞中的钙调磷酸酶引起免疫抑制。作为局部药物，作用机制是不明确defined.ObjectivesTo测试的假设，即皮肤浸润淋巴细胞直接靶向时，钙调磷酸酶抑制剂应用于skin.MethodsTen特应性皮炎患者进行了治疗与1%吡美莫司霜每日两次，以靶向病变。在开始治疗前和治疗后48小时进行皮肤活检。我们评估的细胞定位的NFAT 1和NFAT 2作为一个替代措施的细胞内钙调磷酸酶活性（例如，增加细胞质定位与增加钙调磷酸酶抑制）。如前所述，NFAT 2定位于滤泡角质形成细胞，其活化被局部吡美莫司部分抑制。发现NFAT 1由滤泡和滤泡间角质形成细胞表达，并且其主要核定位不受局部吡美莫司治疗的影响。NFAT 1和NFAT 2均见于浸润淋巴细胞。然而，使用手动计数以及自动化方法来评估NFAT染色的核强度，我们发现具有核的浸润性白细胞的比例与正常人相比显著降低。结论我们的研究结果表明，局部吡美莫司并不主要通过抑制淋巴细胞中的钙调神经磷酸酶/NFAT轴起作用，而是可能通过其他机制起作用，这可能是通过降低毛囊角质形成细胞中的NFAT 2活性实现的。
P>BackgroundTopically applied calcineurin inhibitors have been shown to be effective in the treatment of atopic dermatitis. When systemically administered, these agents cause immunosuppression via inhibition of calcineurin in lymphocytes. As topical agents, the mechanism of action is poorly defined.ObjectivesTo test the hypothesis that skin-infiltrating lymphocytes are directly targeted when calcineurin inhibitors are applied to the skin.MethodsTen patients with atopic dermatitis were treated with 1% pimecrolimus cream twice daily to target lesions. Skin biopsies were performed before and 48 h after beginning therapy. We assessed the cellular localization of NFAT1 and NFAT2 as a surrogate measure of intracellular calcineurin activity (e.g. increasing cytoplasmic localization with increasing calcineurin inhibition).ResultsAll patients showed a clinical response, at both 48 h and 2 weeks. As previously described, NFAT2 localized to the follicular keratinocytes, and its activation was partially inhibited by topical pimecrolimus. NFAT1 was found to be expressed by follicular and interfollicular keratinocytes, and its mostly nuclear localization was not affected by topical pimecrolimus therapy. Both NFAT1 and NFAT2 were found in the infiltrating lymphocytes. However, using both manual counting as well as an automated method to assess nuclear intensity of NFAT staining, we found that the proportion of infiltrating leucocytes with nuclear ('activated') NFAT did not change following therapy with pimecrolimus.ConclusionsOur results suggest that topical pimecrolimus does not act primarily by inhibiting the calcineurin/NFAT axis in lymphocytes but may instead act by other mechanisms, possibly by decreasing NFAT2 activity in follicular keratinocytes.