Dataset Information

TSG-6 Downregulates IFN-Alpha and TNF-Alpha Expression by Suppressing IRF7 Phosphorylation in Human Plasmacytoid Dendritic Cells.

ABSTRACT: Proinflammatory cytokines such as TNF-? and type I interferons (IFN) are pathogenic signatures of systemic lupus erythematosus, and plasmacytoid dendritic cells (pDCs) play a major role by predominantly producing IFN-?. Given the rise of importance in identifying tumor necrosis stimulated gene 6 (TSG-6) as a key anti-inflammatory regulator, we investigate its function and its ability to counteract proinflammatory cytokine secretion by pDCs in vitro. CpG-A and R837 induced significant endogenous TSG-6 expression in the pDC cell-line GEN2.2. Following recombinant human TSG-6 treatment and CpG-A or R837 stimulation, significant reduction in IFN-? and TNF-? was observed in healthy donors' pDCs, and the same phenomenon was confirmed in GEN2.2. By CD44 blocking assay, we deduced that the suppressive effect of TSG-6 is mediated by CD44, by reducing IRF-7 phosphorylation. Our findings suggest that TSG-6 and its downstream signalling pathway could potentially be targeted to modulate proinflammatory cytokine expression in pDCs.

SUBMITTER: Kui L

PROVIDER: S-EPMC5358455 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

TSG-6 Downregulates IFN-Alpha and TNF-Alpha Expression by Suppressing IRF7 Phosphorylation in Human Plasmacytoid Dendritic Cells.

Kui L L Chan G C GC Lee P P W PP

Mediators of inflammation 20170306

Proinflammatory cytokines such as TNF-<i>α</i> and type I interferons (IFN) are pathogenic signatures of systemic lupus erythematosus, and plasmacytoid dendritic cells (pDCs) play a major role by predominantly producing IFN-<i>α</i>. Given the rise of importance in identifying tumor necrosis stimulated gene 6 (TSG-6) as a key anti-inflammatory regulator, we investigate its function and its ability to counteract proinflammatory cytokine secretion by pDCs in vitro. CpG-A and R837 induced significa ...[more]

PMID: 28367002

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Project description:BackgroundBoth humoral and cellular immune mechanisms are involved in the onset and progression of autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLE via the dysregulation of type I interferon (IFN) production; these cells act together with activated myeloid DCs (mDCs) to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMF in targeting DC functions, especially the IFN response of pDCs.MethodsWe isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-α production.ResultsWe found that treatment with 1-10 μM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs (but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, in pDCs, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation and repressed the AKT activity. In addition, MPA inhibited IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs.ConclusionsOur data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disorders by regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.

Dataset Information

TSG-6 Downregulates IFN-Alpha and TNF-Alpha Expression by Suppressing IRF7 Phosphorylation in Human Plasmacytoid Dendritic Cells.

Publications

TSG-6 Downregulates IFN-Alpha and TNF-Alpha Expression by Suppressing IRF7 Phosphorylation in Human Plasmacytoid Dendritic Cells.

Similar Datasets

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