title: The "Alarmins" HMBG1 and IL-33 Downregulate Structural Skin Barrier Proteins and Impair Epidermal Growth.
abstract: The epidermal-derived "alarmins" high-mobility group box 1 (HMGB1) protein and interleukin-33 (IL-33) are upregulated in patients with atopic dermatitis. How-ever, their capacity as pro-inflammatory cytokines and their derived effects on skin barrier regulation are poorly elucidated. We investigated the impact of HMGB1 and IL-33 on gene transcription, protein expression and epidermal differentiation across 3 distinct keratinocyte in vitro models. Primary keratinocytes from healthy donors were used in submerged monolayer cultures, 3D human epidermis equivalents and 3D human skin equivalents. All keratinocyte models underwent 96-h stimulation with HMGB1 (100 μM) or IL-33 (100 ng/ml) using IL-4 (50 ng/ml) as positive control of regulation and vehicle as negative control. We found that HMGB1 and IL-33 downregulated transcription of several genes from members of the epidermal differentiation complex, including filaggrin. Furthermore, HMGB1 downregulated the expression of the encoded proteins in the upper epidermis. Finally, IL-33 and HMGB1 ultimately led to impaired epidermal growth and maturation. In conclusion, HMGB1 and IL-33 could play a significant role in the atopic dermatitis pathophysiology due to negative regulation of structural proteins, stratum corneum formation and epidermal growth.
authors.affiliation: Department of Dermatology and Venerology, Aarhus University Hospital, Aarhus University , DK-8000 Aarhus, Denmark. uffenygaard@gmail.com, uffenygaard@ki.au.dk, uffenygaard@clin.au.dk.
authors.forename: Uffe
authors.initials: U
authors.lastname: Nygaard
authors.forename: Ellen H
authors.initials: EH
authors.lastname: van den Bogaard
authors.forename: Hanna
authors.initials: H
authors.lastname: Niehues
authors.forename: Malene
authors.initials: M
authors.lastname: Hvid
authors.forename: Mette
authors.initials: M
authors.lastname: Deleuran
authors.forename: Claus
authors.initials: C
authors.lastname: Johansen
authors.forename: Christian
authors.initials: C
authors.lastname: Vestergaard
mesh_terms: D000067531:Alarmins / Q000378:metabolism / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004817:Epidermis / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D000091344:Filaggrin Proteins; D024243:HMGB1 Protein / Q000378:metabolism / Q000494:pharmacology*; D064368:Healthy Volunteers; D006801:Humans; D000067596:Interleukin-33 / Q000378:metabolism / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000067531:Alarmins; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C506536:IL33 protein, human; D000067596:Interleukin-33; D012333:RNA, Messenger