Division of Dermatology, Department of Medicine, University of California, San Diego, San Diego, CA, USA.
J Invest Dermatol. 2010 May;130(5):1297-306. doi: 10.1038/jid.2009.435. Epub 2010 Jan 21.
Cathelicidin has dual functions in the skin, acting as an innate antibiotic and as an immunomodulator in diseases such as rosacea and psoriasis. The serine proteases kallikrein 5 (KLK5) and kallikrein 7 (KLK7) control enzymatic processing of cathelicidin precursor in the skin and regulate the eventual function of the final forms of these peptides. We analyzed factors that control expression of KLK5 and KLK7 in normal human epidermal keratinocytes to better understand how these may influence cathelicidin processing and function. Increased extracellular calcium-induced KLK5 and KLK7 mRNA expression and protein release in a time-dependent manner that is similar to induction of differentiation markers such as keratin 10 and involucrin. However, 1,25(OH)(2) vitamin D(3), 9-cis retinoic acid (RA), and 13-cis RA also induced the KLKs, but the timing and pattern of KLK induction for each were different and distinct from changes in differentiation markers. Increased protease activity and differential processing of cathelicidin accompanied increased KLK expression. These findings show that the expression and activity of KLK are under fine control and can be distinctly influenced by variables such as differentiation, calcium, vitamin D, and RA. Thus, these variables may further control the functions of antimicrobial peptides in the skin.
抗菌肽在皮肤中有双重功能，既是先天抗生素，也是酒渣鼻和银屑病等疾病的免疫调节剂。丝氨酸蛋白酶激肽释放酶 5（KLK5）和激肽释放酶 7（KLK7）控制皮肤中抗菌肽前体的酶解加工，并调节这些肽最终形式的最终功能。我们分析了控制正常人类表皮角质形成细胞中 KLK5 和 KLK7 表达的因素，以更好地了解这些因素如何影响抗菌肽的加工和功能。细胞外钙离子诱导 KLK5 和 KLK7 mRNA 表达和蛋白释放呈时间依赖性，类似于角蛋白 10 和兜甲蛋白等分化标志物的诱导。然而，1,25（OH）（2）维生素 D（3）、9-顺式视黄酸（RA）和 13-顺式 RA 也诱导了 KLKs，但每种 KLK 的诱导时间和模式不同，与分化标志物的变化也不同。蛋白酶活性增加和抗菌肽的差异加工伴随着 KLK 表达的增加。这些发现表明 KLK 的表达和活性受到精细控制，并且可以明显受到分化、钙、维生素 D 和 RA 等变量的影响。因此，这些变量可能进一步控制皮肤中抗菌肽的功能。
