Abstract
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.
Highlights
Glucocorticoids have potent anti-inflammatory and anti-proliferative activity, and are the most frequently prescribed drugs for the treatment of various skin diseases including psoriasis and atopic dermatitis [1, 2]
kallikrein-related peptidase 6 (KLK6) expression is induced in mouse and human skin during chronic glucocorticoid treatment
These findings were confirmed by Western blot (Figure 1b) and immunostaining that showed non-detectable KLK6 levels in the interfollicular epidermis (IFE) of control mice and multiple KLK6-positive suprabasal keratinocytes after long-term fluocinolone acetonide (FA) treatment (Figure 1d)
Summary
Glucocorticoids have potent anti-inflammatory and anti-proliferative activity, and are the most frequently prescribed drugs for the treatment of various skin diseases including psoriasis and atopic dermatitis [1, 2]. Chronic use of topical corticosteroids is associated with adverse effects, the major one being skin atrophy. Steroid-induced skin atrophy involves epidermis, dermis, epidermal appendages and subcutaneous fat [1, 3,4,5,6]. It is characterized by epidermal thinning, decreased number and size of keratinocytes, diminished stratum corneum and intercellular lipid lamella, which together with atrophic changes in other skin compartments result in decreased skin barrier function. Steroid tachyphylaxis in patients is well documented, even though in some cases it may reflect irregular steroid use [8, 9, 12,13,14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
