IL-17 downregulates filaggrin and affects keratinocyte expression of genes associated with cellular adhesion.
Atopic eczema and psoriasis are common skin diseases. While it is well established that the pathogenesis of these diseases varies, both are characterized by impairment in epidermal barrier function and abnormal IL-17 expression in the skin and peripheral blood. Recent findings indicated that filaggrin is essential during barrier formation and its insufficiency underlies the pathogenesis of atopic eczema. Filaggrin downregulation has also been reported in psoriasis. It is clear that Th1/Th2 bias influences expression of the protein, but an analysis of the effects of interleukin-17 (IL-17) on the expression of the protein and profilaggrin-processing enzymes has not yet been reported. In addition, the effect of the cytokine on components of functional epidermal barrier, tight junctions and adhesion/desmosomal proteins, has not been elucidated. Keratinocytes were exposed to interleukin-17A, and microarray analysis was performed. Filaggrin protein level was assessed by western blot. We have observed a significant decrease in profilaggrin mRNA level in interleukin-17A-exposed cultures (P = 0.008). Expression of processing enzymes was also altered, indicating an indirect effect of the cytokine on filaggrin production/degradation. Moreover, expression of many genes involved in cellular adhesion was also decreased. A significant downregulation of filaggrin at the protein level was detected by western blot in immortal and primary keratinocytes. Gene ontology analysis indicated changes in keratinization, epidermal differentiation and formation of the cornified envelope. We conclude that IL-17A downregulates the expression of filaggrin and genes important for cellular adhesion which could affect epidermal barrier formation. This effect potentially contributes to barrier dysfunction and could become a possible therapeutic target.
MRC Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Oxford, UK. danuta.gutowska-owsiak@ndm.ox.ac.uk
Danuta
D
Gutowska-Owsiak
Anna L
AL
Schaupp
Maryam
M
Salimi
Tharini A
TA
Selvakumar
Tess
T
McPherson
Stephen
S
Taylor
Graham S
GS
Ogg
D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002154:Calpain / Q000235:genetics; D002401:Cathepsin B / Q000235:genetics; D002402:Cathepsin D / Q000235:genetics; D056668:Cathepsin L / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D057167:Claudins / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics*; D000091344:Filaggrin Proteins; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology*; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D009418:S100 Proteins / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein; D051185:gamma Catenin / Q000235:genetics / Q000378:metabolism
C473255:CLDN7 protein, human; D015820:Cadherins; D015815:Cell Adhesion Molecules; D057167:Claudins; D003598:Cytoskeletal Proteins; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D020381:Interleukin-17; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D009418:S100 Proteins; C569042:TJP1 protein, human; C569046:TJP2 protein, human; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein; D051185:gamma Catenin; D002154:Calpain; C533912:CTSB protein, human; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C527669:CAPNS1 protein, human; C533922:CTSD protein, human; D002402:Cathepsin D