Th2 cytokines act on S100/A11 to downregulate keratinocyte differentiation.
Atopic dermatitis (AD) is an inflammatory skin disease associated with frequent skin infection and impaired skin barrier function. Recent studies indicate that increased Th2 cytokine expression contributes to reduction in antimicrobial peptides and reduced filaggrin (FLG) expression, however, the mechanisms leading to this effect is unknown. Using proteomics, we found the S100 calcium-binding protein A11 (S100/A11) to be significantly downregulated in the presence of IL-4 and IL-13. Culturing keratinocytes with increased calcium concentrations significantly induced S100/A11 expression. This corresponded with an increase in human beta-defensin (HBD)-3 and FLG expression. Interference of S100/A11 expression, by siRNA, inhibited induction of HBD-3 and FLG. Furthermore p21, a cyclin-dependent kinase inhibitor downstream of S100/A11, was required for calcium-mediated induction of HBD-3 and FLG. Importantly, transduction of p21-recombinant protein into keratinocytes prevented IL-4/IL-13-mediated inhibition of FLG and HBD-3 expression. S100/A11 and p21 gene expression was also found to be significantly lower in acute and chronic AD skin. This study demonstrates an important role for S100/A11 and p21 in regulating skin barrier integrity and the innate immune response.
Howell
Michael D
MD
Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
Fairchild
Heather R
HR
Kim
Byung Eui
BE
Bin
Lianghua
L
Boguniewicz
Mark
M
Redzic
Jasmina S
JS
Hansen
Kirk C
KC
Leung
Donald Y M
DY
D000208:Acute Disease; D000328:Adult; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D002908:Chronic Disease; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000378:metabolism / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D000091344:Filaggrin Proteins; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D007381:Intermediate Filament Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009418:S100 Proteins / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism*; D023083:beta-Defensins / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C422950:DEFB103A protein, human; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D018793:Interleukin-13; D007381:Intermediate Filament Proteins; D009418:S100 Proteins; D023083:beta-Defensins; C072337:S100A11 protein, human; D015847:Interleukin-4; D002118:Calcium