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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
Author(s) -
Eljaafari Assia,
Tartelin MarieLaure,
Aissaoui Hanaa,
Chevrel Guillaume,
Osta Bilal,
Lavocat Fabien,
Miossec Pierre
Publication year - 2012
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.34391
Subject(s) - mesenchymal stem cell , interleukin 17 , tumor necrosis factor alpha , peripheral blood mononuclear cell , t cell , immunology , bone marrow , chemistry , cancer research , cytokine , biology , microbiology and biotechnology , immune system , biochemistry , in vitro
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. Conclusion 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.

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