title: The bacterial preparation OK432 induces IL-12p70 secretion in human dendritic cells in a TLR3 dependent manner.
abstract: Dendritic cells (DC) used in therapeutic cancer immunotherapy have to be able to stimulate T cells resulting in an immune response that can efficiently target the cancer cells. One of the critical hurdles has been the lack of IL-12p70 production when maturating the DC, which is rectified by using the bacterial preparation OK432 (trade name Picibanil) to mature the cells. In order to identify the mechanism behind OK432 stimulation of DC, we investigated the contribution of different TLR to examine their involvement in IL-12p70 production. By combining different inhibitors of TLR signaling, we demonstrate here that TLR3 is responsible for the IL-12p70 production of DC induced by OK432. Moreover, our data suggest that the ligand triggering IL-12p70 secretion upon TLR3 stimulation is sensitive to proteinase and partly also RNAse treatment. The fact that a bacterial compound like OK432 can activate the TLR3 pathway in human DC is a novel finding. OK432 demonstrates a critical ability to induce IL-12p70 production, which is of great relevance in DC based cancer immunotherapy.
authors.affiliation: Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway.
authors.forename: Arnt-Ove
authors.initials: AO
authors.lastname: Hovden
authors.forename: Marie
authors.initials: M
authors.lastname: Karlsen
authors.forename: Roland
authors.initials: R
authors.lastname: Jonsson
authors.forename: Silke
authors.initials: S
authors.lastname: Appel
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D002738:Chloroquine / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055785:Gene Knockdown Techniques; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism*; D008024:Ligands; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010844:Picibanil / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000737:chemistry*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D008024:Ligands; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D018664:Interleukin-12; D010844:Picibanil; D012313:RNA; D002738:Chloroquine