Research Papers:

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

Mari Kishibe, Gleb Baida, Pankaj Bhalla, Robert M. Lavker, Bethanee Schlosser, Sin Iinuma, Shigetaka Yoshida, Joel T. Dudley and Irina Budunova _

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Oncotarget. 2016; 7:69479-69488. https://doi.org/10.18632/oncotarget.9926

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Mari Kishibe1, Gleb Baida2, Pankaj Bhalla2, Robert M. Lavker2, Bethanee Schlosser2, Sin Iinuma1, Shigetaka Yoshida3, Joel T. Dudley4, Irina Budunova2

1Department Dermatology, Asahikawa Medical University, Japan

2Department Dermatology, Northwestern University, Chicago, IL, USA

3Department Functional Anatomy and Neuroscience, Asahikawa Medical University, Japan

4Department Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Correspondence to:

Irina Budunova, email: [email protected]

Keywords: glucocorticoid, glucocorticoid receptor, skin atrophy, tachyphylaxis, kallikrein 6

Received: April 5, 2016     Accepted: May 13, 2016     Published: June 8, 2016


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.

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