28 research outputs found
Stimulated T cells generate microparticles, which mimic cellular contact activation of human monocytes: differential regulation of pro- and anti-inflammatory cytokine production by high-density lipoproteins.
No full textImbalance in cytokine homeostasis plays an important part in the pathogenesis of chronic inflammatory diseases such as multiple sclerosis and rheumatoid arthritis. We demonstrated that T cells might exert a pathological effect through direct cellular contact with human monocytes/macrophages, inducing a massive up-regulation of the prototypical proinflammatory cytokines IL-1beta and TNF. This mechanism that might be implicated in chronic inflammation is specifically inhibited by high-density lipoproteins (HDL). Like many other stimuli, besides proinflammatory cytokines, the contact-mediated activation of monocytes induces the production of cytokine inhibitors such as the secreted form of the IL-1 receptor antagonist (sIL-1Ra). The present study demonstrates that stimulated T cells generate microparticles (MP) that induce the production of TNF, IL-1beta, and sIL-1Ra in human monocytes; the production of TNF and IL-1beta but not that of sIL-1Ra is inhibited in the presence of HDL. The results were similar when monocytes were stimulated by whole membranes of T cells or soluble extracts of the latter. This suggests that MP carry similar monocyte-activating factors to cells from which they originate. Thus, by releasing MP, T cells might convey surface molecules similar to those involved in the activation of monocytes by cellular contact. By extension, MP might affect the activity of cells, which are usually not in direct contact with T cells at the inflammatory site. Furthermore, this study demonstrates that HDL exert an anti-inflammatory effect in nonseptic activation of human monocytes, not only by inhibiting the production of IL-1beta and TNF but also, by leaving sIL-1Ra production unchanged
Le HDL modulano il rilascio di citochine da parte di monociti stimolati con microparticelle.
No full textIsolamento e caratterizzazione di microparticelle di origine cellulare dal liquido sinoviale
No full textHepatocyte Growth Factor Limits Autoimmune Neuroinflammation via Glucocorticoid-Induced Leucine Zipper Expression in Dendritic Cells
No full textAutoimmune neuroinflammation, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), a prototype for T cell-mediated autoimmunity, is believed to result from immune tolerance dysfunction leading to demyelination and substantial neurodegeneration. We previously showed that CNS-restricted expression of hepatocyte growth factor (HGF), a potent neuroprotective factor, reduced CNS inflammation and clinical deficits associated with EAE. In this study, we demonstrate that systemic HGF treatment ameliorates EAE through the development of tolerogenic dendritic cells (DCs) with high expression levels of glucocorticoid-induced leucine zipper (GILZ), a transcriptional repressor of gene expression and a key endogenous regulator of the inflammatory response. RNA interference-directed neutralization of GILZ expression by DCs suppressed the induction of tolerance caused by HGF. Finally, adoptive transfer of HGF-treated DCs from wild-type but not GILZ gene-deficient mice potently mediated functional recovery in recipient mice with established EAE through effective modulation of autoaggressive T cell responses. Altogether, these results show that by inducing GILZ in DCs, HGF reproduces the mechanism of immune regulation induced by potent immunomodulatory factors such as IL-10, TGF-β1, and glucocorticoids and therefore that HGF therapy may have potential in the treatment of autoimmune dysfunctions
Glatiramer acetate treatment negatively regulates type I interferon signaling
No full textObjectiveGlatiramer acetate (GA; Copaxone), a disease-modifying therapy for multiple sclerosis (MS), promotes development of anti-inflammatory (M2, type II) monocytes that can direct differentiation of regulatory T cells. We investigated the innate immune signaling pathways that participate in GA-mediated M2 monocyte polarization.MethodsMonocytes were isolated from myeloid differentiation primary response gene 88 (MyD88)-deficient, Toll-IL-1 receptor domain-containing adaptor inducing interferon (IFN)-β (TRIF)-deficient, IFN-α/β receptor subunit 1 (IFNAR1)-deficient, and wild-type (WT) mice and human peripheral blood. GA-treated monocytes were stimulated with Toll-like receptor ligands, then evaluated for activation of kinases and transcription factors involved in innate immunity, and secretion of proinflammatory cytokines. GA-treated mice were evaluated for cytokine secretion and susceptibility to experimental autoimmune encephalomyelitis.ResultsGA-mediated inhibition of proinflammatory cytokine production by monocytes occurred independently of MyD88 and nuclear factor-κB, but was blocked by TRIF deficiency. Furthermore, GA did not provide clinical benefit in TRIF-deficient mice. GA inhibited activation of p38 mitogen-activated protein kinase, an upstream regulator of activating transcription factor (ATF)-2, and c-Jun N-terminal kinase 1, which regulates IFN regulatory factor 3 (IRF3). Consequently, nuclear translocation of ATF-2 and IRF3, components of the IFN-β enhanceosome, was impaired. Consistent with these observations, GA inhibited production of IFN-β in vivo in WT mice, but did not modulate proinflammatory cytokine production by monocytes from IFNAR1-deficient mice.ConclusionOur results demonstrate that GA inhibits the type I IFN pathway in M2 polarization of monocytes independently of MyD88, providing an important mechanism connecting innate and adaptive immune modulation in GA therapy and valuable insight regarding its potential use with other MS treatments
Glatiramer acetate-induced type II monocytes influence the differentiation of naive T-cells
No full textCharacterisation of signal transduction pathways involved in glatiramer acetate (copolymer-1, Copaxone)-induced type II monocyte differentiation
No full textAntibody response in MOG(35-55) induced EAE.
No full textNeurological deficit in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis is widely considered to be a consequence of synergistic T and B cell responses to central nervous system (CNS) antigens. We show that mice immunized with encephalitogenic myelin oligodendrocyte glycoprotein (MOG(35-55)) peptide develop significant serum levels of anti-MOG antibodies in parallel with disease progression. Furthermore, EAE mice developed antibodies against DNA and RNA, a serological hallmark observed in autoimmune diseases such as systemic lupus erythematosus. The presence of anti-nucleic responsive B cells and antibodies during EAE may highlight a previously unappreciated mechanism in the pathogenesis of CNS autoimmunity
Multiple Sclerosis: Glatiramer Acetate Differentially Regulates Monocytic Production of IL-1b and IL-1 Receptor Antagonist
No full textAdditional file 1: Figure S1. of Activation of human B cells negatively regulates TGF-β1 production
No full textB cell activation reduced TGF-β1 mRNA expression. a A representative gating of naïve and memory B cells in PBMCs is shown. Cells were first gated for singlets (FSC-H vs. FSC-A) and lymphocytes (SSC-A vs. FSC-A), followed by a live/dead gate. Naïve B cells (CD27–) and resting and activated memory B cells (CD27+) were distinguished by CD19 versus CD27 gating. FSC-H, forward scatter height; FSC-A, forward scatter area; SSC-A, side scatter area. b Scatter plot indicates mean (± SEM) percentages of naïve (CD27–) versus memory (CD27+) B cell subpopulations (n = 6). c Quantitative RT-PCR analysis of human B cells for the expression of TGF-β1. Expression levels are normalized using the ΔΔCt method, relative to β-actin. Results show mean of 6 independent sets of samples. Errors bars represent SEM. (DOCX 286 kb
