title: Bone marrow-derived and synovium-derived mesenchymal cells promote Th17 cell expansion and activation through caspase 1 activation: contribution to the chronicity of rheumatoid arthritis.
abstract: OBJECTIVE
  Th17 cells have been implicated in rheumatoid arthritis (RA). We hypothesized that the interaction of T cells with bone marrow-derived mesenchymal stem cells (BM-MSCs) or with fibroblast- like synoviocytes (FLS) might, with the help of T cell-secreted inflammatory cytokines (i.e., interleukin-17A [IL-17A], tumor necrosis factor α [TNFα], and/or interferon-γ [IFNγ]), promote Th17 cell expansion and activation.
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMCs) from healthy blood donors were cocultured with BM-MSCs or FLS from RA patients or osteoarthritis (OA) patients. Cocultures were exposed to phytohemagglutinin with or without IL-17A, TNFα, or IFNγ. Quantitative reverse transcription-polymerase chain reaction analysis, enzyme-linked immunosorbent assay, and cytofluorometry were used to measure IL-17A production.
  
  
  RESULTS
  Interaction of PBMCs with BM-MSCs inhibited Th1 and Th2 responses, but promoted Th17 cell expansion, as early as 24 hours, as demonstrated by increases in retinoic acid receptor-related orphan nuclear receptor γ or IL-17A messenger RNA (mRNA) levels, IL-17A secretion levels, and IL-17A-secreting cell frequency, as well as by T cell switching to the Th17 pathway after 2 rounds of stimulation with MSCs. IL-17A production was also increased in PBMCs stimulated with anti-CD3 plus anti-CD28 or in isolated CD3+ or CD45RO+ T cells, thus demonstrating the role of T cell activation. Levels of mRNA for IL-6, IL-8, and IL-1β were further amplified when T cell-secreted inflammatory cytokines were added. Interestingly, OA FLS or RA FLS also enhanced IL-17A and IL-6 production, but only RA FLS enhanced IFNγ and IL-1β production. We further demonstrated that MSC-mediated Th17 promotion requires caspase 1 activation by using an inhibitory peptide and measuring its activity.
  
  
  CONCLUSIONS
  We found that the interaction of MSCs or FLS with T cells promotes the activation and expansion of Th17 cells through caspase 1 activation. Since proinflammatory and T cell-secreted inflammatory cytokines are also amplified, this mechanism may participate in the chronicity of RA.
authors.affiliation: Edouard Herriot Hospital, Immunogenomics and Inflammation Unit, EA4130, Hospices Civils de Lyon, and University Claude Bernard, Lyon, France. aeljaafari@aol.com
authors.forename: Assia
authors.initials: A
authors.lastname: Eljaafari
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Tartelin
authors.forename: Hanaa
authors.initials: H
authors.lastname: Aissaoui
authors.forename: Guillaume
authors.initials: G
authors.lastname: Chevrel
authors.forename: Bilal
authors.initials: B
authors.lastname: Osta
authors.forename: Fabien
authors.initials: F
authors.lastname: Lavocat
authors.forename: Pierre
authors.initials: P
authors.lastname: Miossec
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D020170:Caspase 1 / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D058504:Th17 Cells / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D020170:Caspase 1