Topical treatment with the vitamin D analogue calcipotriol enhances the upregulation of the antimicrobial protein hCAP18/LL-37 during wounding in human skin in vivo.
Cathelicidin antimicrobial protein, hCAP18, is the sole cathelin protein in human. Its C-terminal peptide, which is released enzymatically from the holoprotein, has broad antimicrobial activity but also has effects on eukaryotic cells. hCAP18 is present in leukocytes and is produced at epithelial interfaces as part of the innate immune system. In normal intact skin, there is low constitutive expression of hCAP18, which is rapidly upregulated upon injury. Accumulating evidence indicates that hCAP18/LL-37 may serve a key role in protecting the integrity of the epithelium and also actively promote re-epithelialization and tissue repair. Molecular mechanisms responsible for controlling hCAP18 gene expression in vivo are only partly understood. Vitamin D(3) and its analogue calcipotriol were recently found to directly induce transcription of the hCAP18 gene via functional vitamin D responsive elements in the hCAP18 gene promoter. Skin is the major source for vitamin D(3) in human, where its production is dependent on ultraviolet B (UVB) radiation. We have shown that exposure to UVB, sufficient to produce vitamin D(3), upregulates hCAP18 in human skin in vivo. In the present study, we demonstrate that the upregulation of hCAP18/LL-37 following acute skin injury is further enhanced, at both hCAP18 mRNA and protein levels, after topical treatment with the vitamin D(3) analogue calcipotriol. In chronic ulcers, calcipotriol treatment upregulated hCAP18 mRNA, whereas no consistent upregulation of hCAP18 protein was detected. Our results further support the role of vitamin D(3) as a key physiologic regulator of hCAP18/LL-37 in human skin.
Heilborn
Johan D
JD
Dermatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Weber
Günther
G
Grönberg
Alvar
A
Dieterich
Christine
C
Ståhle
Mona
M
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D000287:Administration, Topical; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D003879:Dermatologic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007871:Leg Ulcer / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics; D014807:Vitamin D / Q000031:analogs & derivatives*; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology; D014947:Wounds and Injuries / Q000188:drug therapy / Q000378:metabolism*; D055815:Young Adult; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D003879:Dermatologic Agents; D014807:Vitamin D; C055085:calcipotriene; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D054804:Cathelicidins