Ingenol mebutate induces a tumor cell-directed inflammatory response and antimicrobial peptides thereby promoting rapid tumor destruction and wound healing.
Ingenol mebutate induces a tumor cell-directed inflammatory response and antimicrobial peptides thereby promoting rapid tumor destruction and wound healing.
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DOI：
10.1186/s40001-018-0343-8
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发表时间：
2018-09-28
影响因子：
4.2
通讯作者：
Gerber PA
中科院分区：
文献类型：
--
作者：
Braun SA;Baran J;Schrumpf H;Buhren BA;Bölke E;Homey B;Gerber PA
Ingenol mebutat（IM）-凝胶可有效用于上皮肿瘤的局部治疗，包括光化性角化病（AK）或肛门生殖器疣（AGW）。与周围光化损伤的皮肤相比，接受IM治疗的AK患者在先前临床可见或可触及的AK的视野中发生了强化的炎症反应，表明诱导了肿瘤细胞导向的炎症。用IM治疗的AGW患者发展甚至更强的炎症反应，伴有大的糜烂，表明针对HPV感染的角质形成细胞的直接炎症反应。值得注意的是，即使是广泛的糜烂愈合非常快，没有任何重复感染。在这里，我们着手阐明这些临床观察的潜在分子和细胞机制。IM的影响（10−9-10−5 M）关于一套全面的趋化因子的表达和翻译（CXCL 1、CXCL 8、CXCL 9、CXCL 10、CXCL 11、CXCL 14、CCL 2、CCL 5、CCL 20、CCL 27）和抗微生物肽（AMP）通过RT-qPCR和ELISA在体外分析原代人上皮角质形成细胞（HEK）和一组上皮癌细胞系中的HBD 1、HBD 2、HBD 3、LL 37、RNase 7。为了研究不同浓度的IM对迁移反应和伤口愈合反应的可能影响，对HEK进行了体外划痕试验。Ingenol mebutat显著且剂量依赖性地诱导HEK和上皮癌细胞系中促炎趋化因子（CXCL 8、CCL 2）和AMP（RNase 7、HBD 3）的表达。与HEK相比，在我们测试的肿瘤细胞中观察到CXCL 8和CCL 2的显著更强的诱导。对于任何测试浓度（10−9、10−8、10−6 M），我们均未观察到IM对HEK迁移和体外伤口愈合反应的任何显著影响，但10−7 M除外，其诱导了显著抑制。我们的数据表明，与分化的HEK相比，肿瘤细胞对IM更敏感。这通过更强的IM介导的肿瘤细胞中促炎趋化因子的诱导是明显的，这可能导致肿瘤细胞导向的炎症反应和快速的肿瘤破坏。此外，IM在角质形成细胞中诱导AMP，并且似乎不会严重干扰角质形成细胞迁移，这有助于快速且简单的伤口愈合。令人惊讶的是，IM在10 - 7 M的浓度下选择性抑制角质形成细胞迁移，这表明IM诱导的生物效应非常依赖于剂量。
Ingenol mebutat (IM)-gel is effective for the topical treatment of epithelial tumors, including actinic keratoses (AKs) or anogenital warts (AGW). AK patients treated with IM develop intensified inflammatory reactions on sights of prior clinical visible or palpable AKs as compared to the surrounding actinically damaged skin, suggesting the induction of a tumor cell-directed inflammation. AGW patients treated with IM develop even stronger inflammatory reactions with large erosions, suggesting a directed inflammatory response against HPV-infected keratinocytes. Of note, even widespread erosions heal very fast without any superinfections. Here, we set out to elucidate underlying molecular and cellular mechanisms of these clinical observations. The effects of IM (10−9–10−5 M) on the expression and translation of a comprehensive set of chemokines (CXCL1, CXCL8, CXCL9, CXCL10, CXCL11, CXCL14, CCL2, CCL5, CCL20, CCL27) and antimicrobial peptides (AMP) (HBD1, HBD2, HBD3, LL37, RNase7) were analyzed in primary human epithelial keratinocytes (HEK) and a set of epithelial cancer cell lines by RT-qPCR and ELISA in vitro. To study the possible effects of different concentrations of IM on migratory, respectively wound healing responses, an in vitro scratch assay was conducted on HEK. Ingenol mebutat significantly and dose-dependently induced the expression of proinflammatory chemokines (CXCL8, CCL2) and AMP (RNase7, HBD3) in HEK and epithelial cancer cell lines. A significantly stronger induction of CXCL8 and CCL2 was observed in our tested tumor cells as compared to HEK. We did not observe any significant effect of IM on HEK migration, respectively wound healing responses in vitro for any tested concentration (10−9, 10−8, 10−6 M) except 10−7 M, which induced a significant inhibition. Our data suggest that tumor cells are more susceptible to IM as compared to differentiated HEK. This is evident by a stronger IM-mediated induction of proinflammatory chemokines in tumor cells, which may result in a tumor cell-directed inflammatory response and rapid tumor destruction. In addition, IM induces AMP in keratinocytes and seems not to severely interfere with keratinocyte migration, which contributes to a fast and uncomplicated wound healing. Surprising is a selective inhibition of keratinocyte migration by IM at the concentration of 10−7 M pointing to very dose depending biological effects, induced by IM.
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影响因子：
3.7
作者：
Gerber PA;Hevezi P;Buhren BA;Martinez C;Schrumpf H;Gasis M;Grether-Beck S;Krutmann J;Homey B;Zlotnik A
通讯作者：
Zlotnik A
影响因子：
5.7
作者：
Freiberger, Sandra N.;Cheng, Phil F.;Hofbauer, Guenther F. L.
通讯作者：
Hofbauer, Guenther F. L.
影响因子：
3.8
作者：
Kontny, E;Ziólkowska, M;Maslinski, W
通讯作者：
Maslinski, W
影响因子：
10.3
作者：
Kreuter, A.;Skrygan, M.;Wieland, U.
通讯作者：
Wieland, U.
影响因子：
4.8
作者：
Harder, J;Bartels, J;Schröder, JM
通讯作者：
Schröder, JM