title: Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9.
abstract: Keratinocytes are continuously in contact with external stimuli and have the capacity to produce several soluble mediators. Pathogen-associated molecular patterns (PAMPs) are recognized, among others, by Toll-like receptors (TLRs). The functional responses of keratinocytes to different PAMPs have not yet been fully established. Here we show that keratinocytes constitutively express TLR1, 2, 3, 4, 5, 6, 9, and 10 mRNA, but not TLR7 and 8. Stimulation of keratinocytes with TLR3, 4, 5, and 9 ligands resulted in differential immune-associated responses. Tumor necrosis factor-alpha, CXC chemokine ligand 8 (CXCL8), CCL2, and C chemokine ligand 20 (CCL20) release was enhanced in response to all PAMPs tested, in a time- and dose-dependent manner. Only TLR9 ligand CpG-oligodeoxynucleotides (ODNs) and TLR3 ligand poly-I:C could additionally induce type I IFNs. CCL27 production was selectively induced by poly-I:C and flagellin, whereas CXCL9 and CXCL10 were exclusively induced by CpG-ODNs and/or poly-I:C. Upregulation of ICAM-1, HLA-DR, HLA-ABC, FasR, and CD40 was mainly observed in response to poly-I:C, flagellin, and lipopolysaccharide. Furthermore, PAMP triggering resulted in the phosphorylation of phosphorylated-IkappaB alpha and in the nucleus translocation of NF-kappaB p65. Altogether, these findings stress an unexpectedly multifaceted role of keratinocytes in innate immunity as evident by their differential, TLR-mediated responses to PAMPs associated with different classes of pathogens.
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Lebre
authors.forename: Angelic M G
authors.initials: AM
authors.lastname: van der Aar
authors.forename: Lisa
authors.initials: L
authors.lastname: van Baarsen
authors.forename: Toni M M
authors.initials: TM
authors.lastname: van Capel
authors.forename: Joost H N
authors.initials: JH
authors.lastname: Schuitemaker
authors.forename: Martien L
authors.initials: ML
authors.lastname: Kapsenberg
authors.forename: Esther C
authors.initials: EC
authors.lastname: de Jong
mesh_terms: D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018925:Chemokines / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism; D018899:CpG Islands; D016207:Cytokines / Q000378:metabolism; D005408:Flagellin / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D009841:Oligonucleotides / Q000235:genetics / Q000494:pharmacology; D010766:Phosphorylation; D011070:Poly I-C / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014018:Tissue Distribution; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; D020672:I-kappa B Proteins; D008024:Ligands; D008070:Lipopolysaccharides; D009841:Oligonucleotides; D020033:Protein Isoforms; D012333:RNA, Messenger; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D005408:Flagellin; D011070:Poly I-C