Kishibe Mari, Baida Gleb, Bhalla Pankaj, Lavker Robert M, Schlosser Bethanee, Iinuma Sin, Yoshida Shigetaka, Dudley Joel T, Budunova Irina
Department of Dermatology, Asahikawa Medical University, Japan.
Department of Dermatology, Northwestern University, Chicago, IL, USA.
Oncotarget. 2016 Oct 25;7(43):69479-69488. doi: 10.18632/oncotarget.9926.
One of the major adverse effects of topical glucocorticoids is cutaneous atrophy often followed by development of resistance to steroids (tachyphylaxis). Previously we showed that after two weeks, interfollicular mouse keratinocytes acquired resistance to anti-proliferative effects of glucocorticoid fluocinolone acetonide (FA). One of the top genes activated by FA during tachyphylaxis was Klk6 encoding kallikrein-related peptidase 6, known to enhance keratinocyte proliferation. KLK6 was also strongly induced by chronic glucocorticoids in human skin. Double immunostaining showed that KLK6+ keratinocytes, localized in suprabasal layer of mouse skin, were frequently adjacent to proliferating 5-bromo-2'-deoxyuridine-positive basal keratinocytes. We used KLK6 knockout (KO) mice to evaluate KLK6 role in skin regeneration after steroid-induced atrophy. KLK6 KOs had thinner epidermis and decreased keratinocyte proliferation. The keratinocytes in wild type and KLK6 KO epidermis were equally sensitive to acute anti-proliferative effect of FA. However, the development of proliferative resistance during chronic treatment was reduced in KO epidermis. This was not due to the changes in glucocorticoid receptor (GR) expression or function as GR protein level and induction of GR-target genes were similar in wild type and KLK6 KO skin. Overall, these results suggest a novel mechanism of epidermal regeneration after glucocorticoid-induced atrophy via KLK6 activation.
外用糖皮质激素的主要不良反应之一是皮肤萎缩，常伴有对类固醇的耐药性（快速耐受）。此前我们发现，两周后，毛囊间小鼠角质形成细胞获得了对糖皮质激素醋酸氟轻松（FA）抗增殖作用的耐药性。在快速耐受过程中，FA激活的最显著基因之一是编码激肽释放酶相关肽酶6的Klk6，已知其可增强角质形成细胞的增殖。慢性糖皮质激素在人类皮肤中也强烈诱导KLK6。双重免疫染色显示，位于小鼠皮肤基底层上方的KLK6 +角质形成细胞经常与增殖的5-溴-2'-脱氧尿苷阳性基底角质形成细胞相邻。我们使用KLK6基因敲除（KO）小鼠来评估KLK6在类固醇诱导萎缩后皮肤再生中的作用。KLK6基因敲除小鼠的表皮更薄，角质形成细胞增殖减少。野生型和KLK6基因敲除小鼠表皮中的角质形成细胞对FA的急性抗增殖作用同样敏感。然而，在慢性治疗期间，基因敲除小鼠表皮中增殖耐药性的发展有所减少。这并不是由于糖皮质激素受体（GR）表达或功能的变化，因为野生型和KLK6基因敲除小鼠皮肤中的GR蛋白水平和GR靶基因的诱导情况相似。总体而言，这些结果表明通过激活KLK6，糖皮质激素诱导萎缩后表皮再生存在一种新机制。
