75 research outputs found
Murine brain endothelial cells differently modulate interferon-γ and interleukin-17 production in vitro
Brain endothelial cells (BEC) are the major constituents of the blood-brain barrier (BBB), the structure that controls entrance of immune cells into CNS parenchyma. Our aim was to investigate the influence of BEC on production of IL-17 and IFN-γ-cytokines that are important for CNS inflammation. To that end, co-cultivations of the bEnd.3 brain endothelial cell line and lymph node cells (LNC) were performed, and gene expression and production of IL-17 and IFN-γ were determined. It was found that bEnd.3 cells inhibited expression and production of IFN-γ, but not of IL-17. Additionally, bEnd.3 cells also reduced production of the major IFN-γ-promoting cytokine - IL-12 - in LNC. The observed variation in modulation of pro-inflammatory cytokines by BEC could be of importance for the understanding of CNS inflammation
Methylprednisolone inhibits IFN-γ and IL-17 expression and production by cells infiltrating central nervous system in experimental autoimmune encephalomyelitis
Methylprednisolone inhibits interleukin-17 and interferon-gamma expression by both naive and primed T cells
<p>Abstract</p> <p>Background</p> <p>Interleukin-17 (IL-17)-producing cells are increasingly considered to be the major pathogenic population in various autoimmune disorders. The effects of glucocorticoids, widely used as therapeutics for inflammatory and autoimmune disorders, on IL-17 generation have not been thoroughly investigated so far. Therefore, we have explored the influence of methylprednisolone (MP) on IL-17 expression in rat lymphocytes, and compared it to the effect of the drug on interferon (IFN)-γ.</p> <p>Results</p> <p>Production of IL-17 in mitogen-stimulated lymph node cells (LNC) from non-treated rats, as well as in myelin basic protein (MBP)-stimulated draining LNC from rats immunized with spinal cord homogenate and complete Freund's adjuvant was significantly reduced by MP. The reduction was dose-dependent, sustained through the follow-up period of 48 hours, and was not achieved through anti-proliferative effect. Additionally, MP inhibited IL-17 production in purified T cells as well, but to less extent than in LNC. In its influence on IL-17 production MP inhibited Ror-γT transcription factor expression, as well as Jun phosphorylation, but not ERK or p38 activation in mitogen-stimulated LNC. Importantly, MP collaborated with IFN-γ in inhibiting IL-17 generation in LNC.</p> <p>Conclusion</p> <p>The observed difference in the effect of MP on IL-17 and IFN-γ could be important for the understanding of the variability in the efficiency of glucocorticoids in the treatment of autoimmune diseases.</p
Micro RNA-155 participates in re-activation of encephalitogenic T cells
MicroRNAs (miR) are small non-coding RNAs involved in the immune
response regulation. miR-155 has been attributed a major
pro-inflammatory role in the pathogenesis of multiple sclerosis and its
animal model experimental autoimmune encephalomyelitis (EAE). Here, a
role of miR-155 in re-activation of encephalitogenic CD4(+) T cells was
investigated. Dark Agouti rats were immunized with myelin basic protein
(MBP) emulsified in complete Freund's adjuvant. CD4(+) T cells were
purified from draining lymph node cells (DLNC) obtained in the inductive
phase and from spinal cord immune cells (SCIC) isolated at the peak of
EAE. CD4(+) T cells obtained from SCIC (i.e., in vivo re-activated
cells) had markedly higher expression of miR-155 in comparison to those
purified from DLNC (not re-activated). Likewise, in vitro re-activation
of DLNC with MBP led to increase in miR-155 expression. Further, DLNC
and DLNC CD4(+) T cells were transfected with an inhibitor of miR-155
during in vitro re-activation. As a result, expression of important
CD4(+) T cell effector cytokines IFN-gamma and IL-17, but not of
regulatory cytokines IL-10 and TGF-beta, was reduced. These results
imply that miR-155 supports re-activation of encephalitogenic CD4+ T
cells. Our results contribute to a view that miR-155 might be a valuable
target in multiple sclerosis therapy. (C) 2015 Elsevier Masson SAS. All
rights reserved.Ministry of Education, Science and Technological Development of the
Republic of Serbia {[}173035, 175038, 173013
Saquinavir-NO Inhibits IL-6 Production in Macrophages
Covalent attachment of the nitric oxide (NO) moiety to the HIV protease
inhibitor Saquinavir (Saq) produced a new chemical entity, named
Saquinavir-NO, (Saq-NO) with reduced toxicity and potent
immunoregulatory influence on T lymphocytes. In this study, we have
compared head-to-head the effects of Saq-NO and Saq on mouse and rat
peritoneal macrophage cytokine secretion and NO production upon in
vitro, ex vivo and in vivo conditions. The results demonstrate that
Saq-NO, but not Saq, potently decreased interleukin (IL)-10, IL-6 and
nitrite accumulation and increased the levels of IL-1 and tumour
necrosis factor (TNF) in supernatants of mouse and rat macrophage
cultures in vitro. Treatment of mice with Saq-NO, but not Saq, inhibited
ex vivo secretion of IL-6 from macrophages. Consistent with these
findings, Saq-NO also reduced blood levels of IL-6 in
lipopolysaccharide-treated mice. The observed inhibitory influence of
Saq-NO on IL-6 generation in macrophages may be involved in the observed
antitumour and immunomodulatory effects of the drug.Ministry of Education and Science of the Republic of Serbia {[}173013,
173035
The H₂S Donor GYY4137 Stimulates Reactive Oxygen Species Generation in BV2 Cells While Suppressing the Secretion of TNF and Nitric Oxide.
GYY4137 is a hydrogen sulfide (H₂S) donor that has been shown to act in an anti-inflammatory manner in vitro and in vivo. Microglial cells are among the major players in immunoinflammatory, degenerative, and neoplastic disorders of the central nervous system, including multiple sclerosis, Parkinson's disease, Alzheimer's disease, and glioblastoma multiforme. So far, the effects of GYY4137 on microglial cells have not been thoroughly investigated. In this study, BV2 microglial cells were stimulated with interferon-gamma and lipopolysaccharide and treated with GYY4137. The agent did not influence the viability of BV2 cells in concentrations up to 200 μM. It inhibited tumor necrosis factor but not interleukin-6 production. Expression of CD40 and CD86 were reduced under the influence of the donor. The phagocytic ability of BV2 cells and nitric oxide production were also affected by the agent. Surprisingly, GYY4137 upregulated generation of reactive oxygen species (ROS) by BV2 cells. The effect was mimicked by another H₂S donor, Na₂S, and it was not reproduced in macrophages. Our results demonstrate that GYY4137 downregulates inflammatory properties of BV2 cells but increases their ability to generate ROS. Further investigation of this unexpected phenomenon is warranted
A Comparative Analysis of Multiple Sclerosis-Relevant Anti-Inflammatory Properties of Ethyl Pyruvate and Dimethyl Fumarate
Dimethyl fumarate (DMF), a new drug for multiple sclerosis (MS)
treatment, acts against neuroinflammation via mechanisms that are
triggered by adduct formation with thiol redox switches. Ethyl pyruvate
(EP), an off-the-shelf agent, appears to be a redox analog of DMF, but
its immunomodulatory properties have not been put into the context of MS
therapy. In this article, we examined and compared the effects of EP and
DMF on MS-relevant activity/functions of T cells, macrophages,
microglia, and astrocytes. EP efficiently suppressed the release of MS
signature cytokines, IFN-gamma and IL-17, from human PBMCs. Furthermore,
the production of these cytokines was notably decreased in
encephalitogenic T cells after in vivo application of EP to rats.
Production of two other proinflammatory cytokines, IL-6 and TNF, and NO
was suppressed by EP in macrophages and microglia. Reactive oxygen
species production in macrophages, microglia activation, and the
development of Ag-presenting phenotype in microglia and macrophages were
constrained by EP. The release of IL-6 was reduced in astrocytes.
Finally, EP inhibited the activation of transcription factor NF-kappa B
in microglia and astrocytes. Most of these effects were also found for
DMF, implying that EP and DMF share common targets and mechanisms of
action. Importantly, EP had in vivo impact on experimental autoimmune
encephalomyelitis, an animal model of MS. Treatment with EP resulted in
delay and shortening of the first relapse, and lower clinical scores,
whereas the second attack was annihilated. Further studies on the
possibility to use EP as an MS therapeutic are warranted.Ministry of Education, Science and Technological Development of the
Republic of Serbia {[}OI173035, OI175038, OI173014, OI173013
Oral neonatal antibiotic treatment perturbs gut microbiota and aggravates central nervous system autoimmunity in Dark Agouti rats.
Gut microbiota dysbiosis has been considered the essential element in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Antibiotics were administered orally to Dark Agouti (DA) rats early in their life with the aim of perturbing gut microbiota and investigating the effects of such intervention on the course of EAE. As a result, the diversity of the gut microbiota was reduced under the influence of antibiotics. Mainly, Firmicutes and Actinobacteria were replaced by Proteobacteria and Bacteroidetes, while decreased proportions of Clostridia and Bacilli classes were accompanied by an increase in Gamma-Proteobacteria in antibiotic-treated animals. Interestingly, a notable decrease in the Helicobacteraceae, Spirochaetaceae and Turicibacteriaceae was scored in antibiotic-treated groups. Also, levels of short chain fatty acids were reduced in the faeces of antibiotic-treated rats. Consequently, aggravation of EAE, paralleled with stronger immune response in lymph nodes draining the site of immunization, and increased inflammation within the CNS, were observed in antibiotic-treated DA rats. Thus, the alteration of gut microbiota leads to an escalation of CNS-directed autoimmunity in DA rats. The results of this study indicate that antibiotic use in early life may have subsequent unfavourable effects on the regulation of the immune system
Mostarica-Stojković M: Murine brain endothelial cells differently modulate interferon-γ and interleukin-17 production in vitro. Arch Biol Sci 2009, 61:29-36. Publish with BioMed Central and every scientist can read your work free of charge "BioMed Central
Abstract — Brain endothelial cells (BEC) are the major constituents of the blood-brain barrier (BBB), the structure that controls entrance of immune cells into CNS parenchyma. Our aim was to investigate the influence of BEC on production of IL-17 and IFN-γ–cytokines that are important for CNS inflammation. To that end, co-cultivations of the bEnd.3 brain endothelial cell line and lymph node cells (LNC) were performed, and gene expression and production of IL-17 and IFN-γ were determined. It was found that bEnd.3 cells inhibited expression and production of IFN-γ, but not of IL-17. Additionally, bEnd.3 cells also reduced production of the major IFN-γ-promoting cytokine – IL-12 – in LNC. The observed variation in modulation of pro-inflammatory cytokines by BEC could be of importance for the understanding of CNS inflammation
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