title: The human cathelicidin LL-37 host defense peptide upregulates tight junction-related proteins and increases human epidermal keratinocyte barrier function.
abstract: Both psoriasis and atopic dermatitis (AD) are not only associated with an impaired stratum corneum barrier, but also with abnormal expression of the tight junction (TJ) proteins. Because host defense peptides, including LL-37, are overexpressed in lesional psoriatic skin but are downregulated in lesional AD skin, we hypothesized that LL-37 might regulate the TJ function in keratinocytes. We demonstrated that LL-37 selectively increased the expression of several claudins and occludin, and enhanced their membrane distribution. Furthermore, LL-37 elevated the transepithelial electrical resistance while reducing the paracellular permeability of keratinocyte layers, and this activity was weakened by the claudin inhibitor ochratoxin A. A characterization of the molecular mechanism underlying the regulation of the TJ barrier by LL-37 revealed that LL-37 induced the activation of the Rac1, atypical PKC, glycogen synthase kinase-3 and PI3K pathways, and the specific inhibition of these pathways reversed the LL-37-mediated regulation of TJ function. In addition, LL-37 enhanced the expression of differentiation markers under the control of ochratoxin A, suggesting an association between LL-37-induced TJ function and keratinocyte differentiation. These data provide novel evidence that, in addition to its antimicrobial and other immunoregulatory functions, LL-37 contributes to cutaneous immunity by strengthening the skin's barrier function.
authors.affiliation: Department of Dermatology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Akiyama
authors.forename: François
authors.initials: F
authors.lastname: Niyonsaba
authors.forename: Chanisa
authors.initials: C
authors.lastname: Kiatsurayanon
authors.forename: Toan The
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ushio
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fujimura
authors.forename: Takashi
authors.initials: T
authors.lastname: Ueno
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.forename: Shigaku
authors.initials: S
authors.lastname: Ikeda
mesh_terms: D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000276:immunology; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis / Q000276:immunology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D057167:Claudins / Q000096:biosynthesis / Q000276:immunology*; D003876:Dermatitis, Atopic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004817:Epidermis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D062793:Occludin / Q000096:biosynthesis / Q000276:immunology*; D009793:Ochratoxins / Q000494:pharmacology; D011565:Psoriasis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019108:Tight Junctions / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*; D054804:Cathelicidins
chemical_list: D000943:Antigens, Differentiation; D023181:Antimicrobial Cationic Peptides; D002121:Calcium Channel Blockers; D057167:Claudins; C568985:OCLN protein, human; D062793:Occludin; D009793:Ochratoxins; C025589:ochratoxin A; D054804:Cathelicidins