title: Oligodeoxynucleotides inhibit Toll-like receptor 3 mediated cytotoxicity and CXCL8 release in keratinocytes.
abstract: Toll-like receptor 3 (TLR3) is an important sensor of viral infections and injury of self in keratinocytes. In this study, we stimulated primary keratinocytes with the TLR3-ligand polyI:C. This induced a toxic effect shown by up-regulation of the alarmin high-mobility group protein B1 and reduced responses in a MTT-assay. PolyI:C was a potent inducer of proinflammatory cytokines, and both these responses and the cytotoxic effects were found to be TLR3 dependent, as demonstrated by the use of siRNA for TLR3. Interestingly, co-stimulation with oligodeoxynucleotides (ODNs) inhibited all polyI:C induced effects. This inhibition was found to be mediated by the competition of endocytic uptake of polyI:C and ODNs. We have found polyI:C induced cytotoxicity and proinflammatory responses to be dependent of TLR3 and that this may be inhibited by ODNs. With these findings, we see a promising potential for ODNs in inhibiting TLR3-induced responses in inflammatory skin disorders.
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. oystein.grimstad@ntnu.no
authors.forename: Oystein
authors.initials: O
authors.lastname: Grimstad
authors.forename: Brita
authors.initials: B
authors.lastname: Pukstad
authors.forename: Jørgen
authors.initials: J
authors.lastname: Stenvik
authors.forename: Terje
authors.initials: T
authors.lastname: Espevik
mesh_terms: D002460:Cell Line; D003521:Cyclopropanes; D004705:Endocytosis; D006151:Guanosine / Q000031:analogs & derivatives; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011070:Poly I-C / Q000494:pharmacology*; D051196:Toll-Like Receptor 3 / Q000819:agonists* / Q000378:metabolism
chemical_list: C508606:CXCL8 protein, human; D003521:Cyclopropanes; D016209:Interleukin-8; C508012:N2-cyclopropylamine-guanosine; D009838:Oligodeoxyribonucleotides; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D006151:Guanosine; D011070:Poly I-C