title: Mycophenolate antagonizes IFN-γ-induced catagen-like changes via β-catenin activation in human dermal papilla cells and hair follicles.
abstract: Recently, various immunosuppressant drugs have been shown to induce hair growth in normal hair as well as in alopecia areata and androgenic alopecia; however, the responsible mechanism has not yet been fully elucidated. In this study, we investigate the influence of mycophenolate (MPA), an immunosuppressant, on the proliferation of human dermal papilla cells (hDPCs) and on the growth of human hair follicles following catagen induction with interferon (IFN)-γ. IFN-γ was found to reduce β-catenin, an activator of hair follicle growth, and activate glycogen synthase kinase (GSK)-3β, and enhance expression of the Wnt inhibitor DKK-1 and catagen inducer transforming growth factor (TGF)-β2. IFN-γ inhibited expression of ALP and other dermal papillar cells (DPCs) markers such as Axin2, IGF-1, and FGF 7 and 10. MPA increased β-catenin in IFN-γ-treated hDPCs leading to its nuclear accumulation via inhibition of GSK3β and reduction of DKK-1. Furthermore, MPA significantly increased expression of ALP and other DPC marker genes but inhibited expression of TGF-β2. Therefore, we demonstrate for the first time that IFN-γ induces catagen-like changes in hDPCs and in hair follicles via inhibition of Wnt/β-catenin signaling, and that MPA stabilizes β-catenin by inhibiting GSK3β leading to increased β-catenin target gene and DP signature gene expression, which may, in part, counteract IFN-γ-induced catagen in hDPCs.
authors.affiliation: Department of Dermatology, Chung-Ang University College of Medicine, Seoul 137-701, Korea. bktsh0328@gmail.com.
authors.forename: Sunhyo
authors.initials: S
authors.lastname: Ryu
authors.affiliation: Department of Dermatology, Chung-Ang University College of Medicine, Seoul 137-701, Korea. iamyonghee84@naver.com.
authors.forename: Yonghee
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Dermatology, Chung-Ang University College of Medicine, Seoul 137-701, Korea. drhmy@naver.com.
authors.forename: Moo Yeol
authors.initials: MY
authors.lastname: Hyun
authors.affiliation: Department of Dermatology, Chung-Ang University College of Medicine, Seoul 137-701, Korea. sun02ya@naver.com.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Dermatology, St. Paul's Hospital, College of Medicine, the Catholic University of Korea, Seoul 137-701, Korea. kwanho16@nate.com.
authors.forename: Kwan Ho
authors.initials: KH
authors.lastname: Jeong
authors.affiliation: Department of Dermatology, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul 137-701, Korea. yymmpark6301@hotmail.com.
authors.forename: Young Min
authors.initials: YM
authors.lastname: Park
authors.affiliation: Department of Dermatology, St. Paul's Hospital, College of Medicine, the Catholic University of Korea, Seoul 137-701, Korea. johnkang@catholic.ac.kr.
authors.forename: Hoon
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Dermatology, Chung-Ang University College of Medicine, Seoul 137-701, Korea. momo920@daum.net.
authors.forename: Kui Young
authors.initials: KY
authors.lastname: Park
authors.affiliation: Department of Dermatology, Denver Health Medical Center, Denver, CO 80204, USA. Cheryl.Armstrong@dhha.org.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Armstrong
authors.affiliation: Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. AJohnson4@uams.edu.
authors.forename: Andrew
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Department of Dermatology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA. peter.song@ucdenver.edu.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Song
authors.affiliation: Department of Dermatology, Chung-Ang University College of Medicine, Seoul 137-701, Korea. beomjoon@unitel.co.kr.
authors.forename: Beom Joon
authors.initials: BJ
authors.lastname: Kim
mesh_terms: D000505:Alopecia / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D018859:Hair Follicle / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D053781:Transforming Growth Factor beta2 / Q000096:biosynthesis / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000502:physiology*
chemical_list: C495270:CTNNB1 protein, human; C501126:DKK1 protein, human; D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; C509041:TGFB2 protein, human; D053781:Transforming Growth Factor beta2; D051176:beta Catenin; D007371:Interferon-gamma; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D009173:Mycophenolic Acid