Important role of kallikrein 6 for the development of keratinocyte proliferative resistance to topical glucocorticoids.
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.
Department of Dermatology, Asahikawa Medical University, Japan.
Mari
M
Kishibe
Department of Dermatology, Northwestern University, Chicago, IL, USA.
Gleb
G
Baida
Department of Dermatology, Northwestern University, Chicago, IL, USA.
Pankaj
P
Bhalla
Department of Dermatology, Northwestern University, Chicago, IL, USA.
Robert M
RM
Lavker
Department of Dermatology, Northwestern University, Chicago, IL, USA.
Bethanee
B
Schlosser
Department of Dermatology, Asahikawa Medical University, Japan.
Sin
S
Iinuma
Department of Functional Anatomy and Neuroscience, Asahikawa Medical University, Japan.
Shigetaka
S
Yoshida
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Joel T
JT
Dudley
Department of Dermatology, Northwestern University, Chicago, IL, USA.
Irina
I
Budunova
D000328:Adult; D000368:Aged; D000818:Animals; D001284:Atrophy / Q000139:chemically induced; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D004817:Epidermis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005446:Fluocinolone Acetonide / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008875:Middle Aged; D012038:Regeneration; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013256:Steroids
D005938:Glucocorticoids; D013256:Steroids; D005446:Fluocinolone Acetonide; C103551:KLK6 protein, human; D007610:Kallikreins; C491223:Prss18 protein, mouse
glucocorticoid; glucocorticoid receptor; kallikrein 6; skin atrophy; tachyphylaxis