Important role of kallikrein 6 for the development of keratinocyte proliferative resistance to topical glucocorticoids

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.

Case of punctate palmoplantar keratoderma type I treated with combination of low‐dose oral acitretin and topical salicylic acid and steroid

“…However, topical steroid has not been reported as a treatment of PPPK. Glucocorticoids can suppress the proliferation of keratinocytes by reducing mitotic rates and thereby have an antiproliferative activity . Chronic use of topical steroid results in epidermal thinning, especially thinning of the stratum corneum, together with atrophic changes .…”

“…Glucocorticoids can suppress the proliferation of keratinocytes by reducing mitotic rates and thereby have an antiproliferative activity. 13 Chronic use of topical steroid results in epidermal thinning, especially thinning of the stratum corneum, together with atrophic changes. 14 We carefully speculate that this mechanism of glucocorticoid may have a therapeutic effect on PPPK which is induced by hyperproliferation of keratinocytes although further researches are needed to confirm this mechanism.…”

Glucocorticoid Resistance: Interference between the Glucocorticoid Receptor and the MAPK Signalling Pathways

“…KLK6 is induced by the phorbol ester PMA, a known inductor of MAPK, and is up-regulated in the skin of patients with several hyperproliferative/inflammatory diseases. Also, KLK6 is also induced upon chronic GC treatment likely as a mechanism aimed to regenerate the epidermis after GC-induced skin atrophy; in agreement with this, Klk6 KO mice showed decreased steroid tachyphylaxis [ 114 ].…”

“…In mice, it was demonstrated that chronic exposure to GCs induced desensitization; instead of the initial rate of growth inhibition (around 10–15% of control level), keratinocyte proliferation returned to the basal levels and even increased after two weeks of treatment [ 113 ]. The activation of kallikrein (KLK)-related peptidase KLK6 may in part be responsible for the development of GC-desensitization [ 114 ]. KLK6 is induced by the phorbol ester PMA, a known inductor of MAPK, and is up-regulated in the skin of patients with several hyperproliferative/inflammatory diseases.…”

Διερεύνηση Του Ρόλου Της Πρωτεάσης ΚLK6 Στη Φλεγμονή Και Στον Καρκίνο Του Δέρματος

“…(Meier, Dear et al, 1999). Επίσης βρέθηκε ότι η επιδερμίδα των Klk6 -/ποντικών είναι υποπολλαπλασιαστική όπως αναφέρθηκε και προηγουμένως (Kishibe, Baida et al, 2016) και παρουσιάζει κανονικά πρότυπα διαφοροποίησης (Zingkou et al, 2019).…”