title: NF-κB, p38 MAPK, ERK1/2, mTOR, STAT3 and increased glycolysis regulate stability of paricalcitol/dexamethasone-generated tolerogenic dendritic cells in the inflammatory environment.
abstract: Tolerogenic dendritic cells (tDCs) may offer an intervention therapy in autoimmune diseases or transplantation. Stable immaturity and tolerogenic function of tDCs after encountering inflammatory environment are prerequisite for positive outcome of immunotherapy. However, the signaling pathways regulating their stable tolerogenic properties are largely unknown. In this study, we demonstrated that human monocyte-derived tDCs established by using paricalcitol (analogue of vitamin D2), dexamethasone and monophosphoryl lipid A exposed for 24h to LPS, cytokine cocktail, polyI:C or CD40L preserved reduced expression of co-stimulatory molecules, increased levels of inhibitory molecules ILT-3, PDL-1 and TIM-3, increased TLR-2, increased secretion of IL-10 and TGF-β, reduced IL-12 and TNF-α secretion and reduced T cell stimulatory capacity. tDCs further induced IL-10-producing T regulatory cells that suppressed the proliferation of responder T cells. In the inflammatory environment, tDCs maintained up-regulated indoleamine 2, 3 dioxygenase but abrogated IκB-α phosphorylation and reduced transcriptional activity of p65/RelA, RelB and c-Rel NF-κB subunits except p50. Mechanistically, p38 MAPK, ERK1/2, mTOR, STAT3 and mTOR-dependent glycolysis regulated expression of ILT-3, PDL-1 and CD86, secretion of IL-10 and T cell stimulatory capacity of tDCs in the inflammatory environment. Stability of tDCs in the inflammatory environment is thus regulated by multiple signaling pathways.
authors.affiliation: Sotio a.s., Prague, Czech Republic.|Department of Immunology, Charles University, 2nd Medical School, Prague, Czech Republic.
authors.forename: Klára
authors.initials: K
authors.lastname: Dáňová
authors.affiliation: Sotio a.s., Prague, Czech Republic.|Department of Immunology, Charles University, 2nd Medical School, Prague, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Klapetková
authors.affiliation: Department of Immunology, Charles University, 2nd Medical School, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Kayserová
authors.affiliation: Department of Immunology, Charles University, 2nd Medical School, Prague, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Šedivá
authors.affiliation: Sotio a.s., Prague, Czech Republic.|Department of Immunology, Charles University, 2nd Medical School, Prague, Czech Republic.
authors.forename: Radek
authors.initials: R
authors.lastname: Špíšek
authors.affiliation: Sotio a.s., Prague, Czech Republic.|Department of Immunology, Charles University, 2nd Medical School, Prague, Czech Republic.
authors.forename: Lenka Palová
authors.initials: LP
authors.lastname: Jelínková
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004872:Ergocalciferols / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D004872:Ergocalciferols; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C084656:paricalcitol; D003907:Dexamethasone; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases
keywords: Immunology and Microbiology Section; activation pathways; glycolysis; immune response; immunity; immunoregulation; stability; tolerogenic DCs