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Topical calcineurin inhibitors compromise stratum corneum integrity, epidermal permeability and antimicrobial barrier function

Authors
 Minjeong Kim  ;  Minyoung Jung  ;  Seung-Phil Hong  ;  Hyerin Jeon  ;  Min-Jung Kim  ;  Mee-Yon Cho  ;  Seung-Hun Lee  ;  Mao-Qiang Man  ;  Peter M. Elias  ;  Eung-Ho Choi 
Citation
 EXPERIMENTAL DERMATOLOGY, Vol.19(6) : 501-510, 2010 
Journal Title
 EXPERIMENTAL DERMATOLOGY 
ISSN
 0906-6705 
Issue Date
2010
MeSH
Adult ; Animals ; Antimicrobial Cationic Peptides/genetics ; Antimicrobial Cationic Peptides/metabolism* ; Calcineurin Inhibitors* ; Cathelicidins/genetics ; Cathelicidins/metabolism ; Cytoplasmic Granules/drug effects ; Cytoplasmic Granules/pathology ; Desmosomes/drug effects ; Desmosomes/pathology ; Electric Impedance ; Enzyme Inhibitors/administration & dosage ; Enzyme Inhibitors/pharmacology* ; Epidermis/drug effects* ; Epidermis/metabolism ; Epidermis/pathology ; Fatty Acid Synthases/genetics ; Female ; Gene Expression/drug effects ; Homeostasis/drug effects ; Humans ; Hydroxymethylglutaryl CoA Reductases/genetics ; Interleukin-1alpha/metabolism ; Lipid Metabolism/drug effects ; Lipids/pharmacology ; Male ; Mice ; Mice, Hairless ; Permeability/drug effects* ; Proliferating Cell Nuclear Antigen/metabolism ; Serine C-Palmitoyltransferase/genetics ; Skin/drug effects ; Skin/metabolism ; Skin/pathology ; Tacrolimus/analogs & derivatives ; Tacrolimus/pharmacology ; Young Adult ; beta-Defensins/genetics ; beta-Defensins/metabolism
Abstract
BACKGROUND: Topical calcineurin inhibitors (TCIs) such as pimecrolimus and tacrolimus have recently been used for dermatologic diseases including atopic dermatitis instead of topical glucocorticoids, because they display comparable efficacy, but less-frequent side effects. Although even short-term topical glucocorticoid compromise epidermal permeability barrier homeostasis, the effects of TCI on barrier function have not yet been reported. However, viral infections such as eczema herpeticum and molluscum contagiosum, which could indicate an impaired skin barrier, continue to occur with TCI use in atopic dermatitis. OBJECTIVES: We determined here whether TCIs disrupt epidermal permeability barrier and antimicrobial function, and whether these effects can be prevented. METHODS AND RESULTS: In normal humans, topical pimecrolimus and tacrolimus applied twice-daily for 5 days, delay barrier recovery without an increase in basal transepidermal water loss was observed. Co-application of physiologic lipid mixture (PLM) containing an equimolar ratio of ceramides, cholesterol and free fatty acids normalized barrier homeostasis in the face of topical TCIs. In hairless mice, 4 days of TCI treatment also disrupted barrier function significantly. TCIs-treated epidermis showed the decrease of epidermal lipid content, lamellar body number and secretion, and lipid synthesis-related enzymes such as 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, serine-palmitoyl transferase and fatty acid synthase, implying decreased lipid synthesis. TCIs also suppressed expression of IL-1alpha and antimicrobial peptides, CRAMP and mouse beta-defensin 3. However, these TCI-induced abnormalities can be overridden by topical replacement with PLM. CONCLUSIONS: Our results demonstrate that TCIs induce negative effects on the skin barrier including permeability and antimicrobial functions, which are mediated by decreasing epidermal lipid synthesis, lamellar body secretion and antimicrobial peptides expression through suppression of cytokine such as IL-1alpha, therefore co-treatment with PLM would be helpful to overcome these negative effects
Files in This Item:
T201001977.pdf Download
DOI
10.1111/j.1600-0625.2009.00941.x
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Seung Hun(이승헌)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/101299
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