scholarly journals Expression and extracellular release of Trx80, the truncated form of thioredoxin, by TNF-α- and IL-1β-stimulated human synoviocytes from patients with rheumatoid arthritis

2007 ◽  
Vol 113 (3) ◽  
pp. 149-155 ◽  
Author(s):  
Hervé Lemarechal ◽  
Phillippe Anract ◽  
Jean-Louis Beaudeux ◽  
Dominique Bonnefont-Rousselot ◽  
Ohvanesse G. Ekindjian ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Cytokines ◽  
Protein Interactions ◽  
Ex Vivo ◽  
Truncated Form ◽  
Experimental Conditions ◽  
Extracellular Release ◽  
Tnf Α ◽  
Factor Α ◽  
Pro Inflammatory Cytokines

Thioredoxin (Trx) plays several important roles, through changes to sulfhydryl reactions and protein interactions, in controlling cellular signalling processes in RA (rheumatoid arthritis). Trx80, the 10 kDa C-terminal truncated form of Trx, is a potent mitogenic cytokine and is involved in the Th1 response. In the present study, we have investigated the ability of synoviocytes from five RA patients to induce Trx80 after ex vivo stimulation by the pro-inflammatory cytokines IL-1β (interleukin-1β) and TNF-α (tumour necrosis factor-α) or by H2O2. Synoviocytes from five OA (osteoarthritis) patients were used as controls. Immunoprecipitation assays using two different antibodies showed that RA, but not OA, cells expressed intact Trx80 protein in culture even when not stimulated. Treatment with pro-inflammatory cytokines alone or in combination enhanced this basal production and induced the extracellular release of Trx80 by all of the RA cells tested. Under our experimental conditions, the rate of Trx80 release from RA cells was approx. 30% of the total Trx produced. In contrast, Trx80 was not detected in response to H2O2 in RA or OA synoviocyte lysates and their respective culture supernatants, indicating that the oxidative process induced by H2O2 in synoviocytes was unable to modify Trx80 release. Moreover, Trx80 induced synoviocyte proliferation as evaluated by [3H]thymidine incorporation. These results highlight the effect of the inflammatory process on the release of both Trx and Trx80 from RA synoviocytes, and suggest that the cytokine-induced increase in Trx80 cell release may constitute a link between inflammation and the immune system in RA.

scholarly journals Kinetics and Interplay of Mediators of Inflammation-Induced Bone Damage in the Course of Adjuvant Arthritis

2013 ◽  
Vol 26 (1) ◽  
pp. 37-48 ◽  
Author(s):  
S.M. Nanjundaiah ◽  
J.P. Stains ◽  
K.D. Moudgil
Keyword(s):  
Bone Remodeling ◽  
Inflammatory Cytokines ◽  
Adjuvant Arthritis ◽  
Bone Erosion ◽  
Experimental Conditions ◽  
Mediators Of Inflammation ◽  
Bone Damage ◽  
Tnf Α ◽  
Kinetics Of ◽  
Pro Inflammatory Cytokines

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation, bone erosion, and cartilage destruction in the joints. It is increasingly being realized that inflammation might play an important role in inducing bone damage in arthritis. However, there is limited validation of this concept in vivo in well-controlled experimental conditions. We addressed this issue using the adjuvant arthritis (AA) model of RA. In AA, the draining lymph nodes are the main sites of activation of pathogenic leukocytes, which then migrate into the joints leading to the induction of arthritis. We tested the temporal kinetics of mediators of bone damage [e.g., receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) and osteopontin (OPN)] and inflammation (pro-inflammatory cytokines and chemokines) in the draining lymph node cells (LNC) at different phases of AA, and then examined their inter-relationships. Our study revealed that, together with cytokines/chemokines, some of the mediators of bone remodeling are also produced in LNC. Various cytokines/chemokines showed distinct kinetics of expression as well as patterns of correlation with mediators of bone remodeling at different phases of the disease. Pro-inflammatory cytokines such as TNF-α are known to play an important role in bone damage. Interestingly, there was a positive correlation between TNF-α and RANKL, between RANKL and each of the 3 chemokines tested (RANTES, MIP-1α, and GRO/KC), and between TNF-α and RANTES. Our results in the AA model lend support to the concept of osteo-immune crosstalk during the course of autoimmune arthritis.

scholarly journals Staphylococcus aureus α-Toxin Induces Inflammatory Cytokines via Lysosomal Acid Sphingomyelinase and Ceramides

2017 ◽  
Vol 43 (6) ◽  
pp. 2170-2184 ◽  
Author(s):  
Jie Ma ◽  
Erich Gulbins ◽  
Michael J. Edwards ◽  
Charles C. Caldwell ◽  
Martin Fraunholz ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Confocal Microscopy ◽  
Inflammatory Cytokines ◽  
Cathepsin B ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Clinical Problem ◽  
Acid Sphingomyelinase ◽  
Tnf Α ◽  
Factor Α

Background/Aims: Staphylococcus aureus (S. aureus) infections are a major clinical problem and range from mild skin and soft-tissue infections to severe and even lethal infections such as pneumonia, endocarditis, sepsis, osteomyelitis, and toxic shock syndrome. Toxins that are released from S. aureus mediate many of these effects. Here, we aimed to identify molecular mechanisms how α-toxin, a major S. aureus toxin, induces inflammation. Methods: Macrophages were isolated from the bone marrow of wildtype and acid sphingomyelinase-deficient mice, stimulated with S. aureus α-toxin and activation of the acid sphingomyelinase was quantified. The subcellular formation of ceramides was determined by confocal microscopy. Release of cathepsins from lysosomes, activation of inflammasome proteins and formation of Interleukin-1β (IL-1β) and Tumor Necrosis Factor-α (TNF-α) were analyzed by western blotting, confocal microscopy and ELISA. Results: We demonstrate that S. aureus α-toxin activates the acid sphingomyelinase in ex vivo macrophages and triggers a release of ceramides. Ceramides induced by S. aureus α-toxin localize to lysosomes and mediate a release of cathepsin B and D from lysosomes into the cytoplasm. Cytosolic cathepsin B forms a complex with Nlrc4. Treatment of macrophages with α-toxin induces the formation of IL-1β and TNF-α. These events are reduced or abrogated, respectively, in cells lacking the acid sphingomyelinase and upon treatment of macrophages with amitriptyline, a functional inhibitor of acid sphingomyelinase. Pharmacological inhibition of cathepsin B prevented activation of the inflammasome measured as release of IL-1β, while the formation of TNF-α was independent of cathepsin B. Conclusion: We demonstrate a novel mechanism how bacterial toxins activate the inflammasome and mediate the formation and release of cytokines: S. aureus α-toxin triggers an activation of the acid sphingomyelinase and a release of ceramides resulting in the release of lysosomal cathepsin B and formation of pro-inflammatory cytokines.

scholarly journals Immunomodulatory Responses Of Toll Like Receptors Against 2019nCoV

2021 ◽  
Vol 10 (2) ◽  
Author(s):  
Amany Sayed Maghraby
Keyword(s):  
Inflammatory Cytokines ◽  
English Language ◽  
Toll Like Receptors ◽  
Complex Molecules ◽  
Ribonucleic Acids ◽  
Histocompatibility Complex ◽  
Tnf Α ◽  
Factor Α ◽  
Molecular Signals ◽  
Pro Inflammatory Cytokines

The present review discusses the immune signals via toll like receptors (TLRs) against 2019nCoV. We researched using different database, up to June 18th, 2020. All the included articles were published in English language. The outcome of this review, that some TLRs agonists or antagonists are progressed as drugs to combat and down regulating TLRs immune signals respectively. TLRs 3 and 4 recognized 2019nCoV spike protein through immune and molecular signals that leading to immune stimulation of pro-inflammatory cytokines and even the immune fever. While the TLRs7 and 8 recognized single-stranded ribonucleic acids (ssRNAs) leading to elevation of the tumour necrosis factor α (TNF-α), interleukin (IL)-6 and -12 levels. TLRs agonists or antagonists utilized as immunotherapeutic targets against 2019nCoV via TLRs signals. Chloroquine and hydroxychloroquine; the approval compounds for 2019nCoV therapy can be inhibiting the class II major histocompatibility complex molecules expression and antigen presentation and even immune suppressions of the pro-inflammatory cytokines profile.

Over-expression of PTEN attenuates the inflammation of fibroblast-like synoviocytes in rheumatoid arthritis

2020 ◽  
Author(s):  
Xiao-Feng Li ◽  
Qing-Qing Xu ◽  
Man-Wen Yang ◽  
He Chen ◽  
Su-Qin Yin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Dna Methylation ◽  
Inflammatory Cytokines ◽  
Pten Expression ◽  
Over Expression ◽  
Tnf Α ◽  
And Migration ◽  
Fibroblast Like Synoviocytes ◽  
Pro Inflammatory Cytokines

Abstract Background: Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and the subsequent destruction of adjacent articular cartilage and bone. Recent studies have shown that phosphatase and tension homolog deleted on chromosome 10 (PTEN) might contribute to the survival of fibroblast-like synoviocytes (FLS) and the production of pro-inflammatory cytokines in RA.Methods : The expression was determined in RA and adjuvant-induced arthritis (AIA) synovial tissues by immunohistochemistry. FLSs were treatment with bpv, PTEN-RNAi or over-expression plasmid in RA and AIA. FLSs migration was assessed. The ad-PTEN was also injected into the knee of AIA in vivo. Chromatin Immunoprecipitation (ChIP) and Methylation-special PCR (MSP) assay were used to study the expression of PTEN mRNA in DNA methylation.Results : Down-regulated level of PTEN expression was observed in RA and AIA. Inhibition PTEN expression by bpv or PTEN-RNAi could promote the expression of pro-inflammatory cytokines, chemokines and migration of FLS with TNF-α in RA and AIA. Consistently, over-expression of PTEN reduced their low-expression of pro-inflammatory cytokines, chemokines and migration. Intra-articular injection of ad-PTEN in AIA knees dramatically reduced inflammatory and paw swelling in vivo. The ChIP and MSP assay has clearly detected the DNA methylation of PTEN was increased in FLS with TNF-α. Moreover, intraperitoneally injected 5-Aza in AIA also suppressed the inflammatory and paws swelling in vivo.Conclusions: Our findings suggest that over-expression PTEN attenuates the formation of pro-inflammatory cytokines, chemokines and migration of FLS, and it may be regulated by DNA methylation in the pathogenesis of RA.

scholarly journals Serum cytokine profile in early and established rheumatoid arthritis

2019 ◽  
Vol 47 (5) ◽  
pp. 393-399
Author(s):  
A. A. Novikov ◽  
Е. N. Aleksandrova ◽  
G. V. Lukina
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Cytokines ◽  
Cytokine Profile ◽  
Serum Cytokine ◽  
Colony Stimulating Factors ◽  
Early Ra ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Background: An important characteristic of immune pathology in rheumatoid arthritis (RA) is a B-cell tolerance defect, associated with autoantibodies production, and antigen-specific activation of Th-1 CD4+ T lymphocytes with an excess production of pro-inflammatory cytokines compared to anti-inflammatory ones. Pro-inflammatory cytokines contribute to the development of local inflammatory effects, induce bone destruction and pannus formation, and contribute to the development of autoimmune abnormalities and systemic manifestations. Anti-inflammatory cytokines are able to reduce the rate of joint destruction. There is evidence of the involvement of Th2 cytokines in the development of early RA. These facts suggest the need for a thorough investigation into the balance between the Th1 and Th2 types of immune response at different stages of the disease.Aim: To assess the importance of сytokine profiling in the evaluation of immune abnormalities in RA.Materials and methods: In this descriptive, controlled, retrospective study, we examined 118 patients with RA and 33 healthy donors as a control group. Serum IgM rheumatoid factor (RF) and C-reactive protein (CRP) levels were measured by immunonephelometry; anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-mutated citrullinated vimentin antibodies (anti-MCV) were determined by an enzyme immunoassay, cytokines levels with "xMAP" technique.Results: Serum cytokine levels vary depending on RA duration. The cytokine profile in early RA, unlike that in established RA with a duration of more than 6 months, is characterized by higher levels of pro-inflammatory (MIP-1α), Th1 (IFN-γ), and Th17 (IL-17) cytokines, colony-stimulating factors (IL-7, G-CSF), and chemokines (IL-8, IP-10) (p < 0.05 for all parameters). In established RA, the levels of pro-inflammatory (IL-1β, -6, -15, TNF-α), anti-inflammatory (IL-1ra, IL-10, IL-13, IL-5), Th1 (IL-2, IL-12), Th2 (IL-9) cytokines and colony-stimulating factors (G-CSF, GM-CSF) correlate with the concentrations of IgM RF and antibodies to citrullinated proteins (antiCCP, anti-MCV) (all p < 0.05). There was also а correlation between CRP and pro-inflammatory (IL-1β, IL-6, TNF-α), Th1 (IL-12), Th2 (IL-5, IL-9) cytokine levels and between DAS28 and pro-inflammatory cytokine (IL-6) and colony-stimulating factor (G-CSF) levels (all p < 0.05). Conclusion: In RA, cytokines, chemokines and colony-stimulating factors mirror the inflammatory activity of the disease. Changes in blood concentrations of cytokines enable to get an insight into the complex interplay of numerous mediators of innate and acquired immunity

scholarly journals Pro-Inflammatory Cytokines at Ultra-Low Dose Exert Anti-Inflammatory Effect In Vitro: A Possible Mode of Action Involving Sub-Micron Particles?

Dose-Response ◽  
2020 ◽  
Vol 18 (4) ◽  
pp. 155932582096172
Author(s):  
Ilaria Floris ◽  
Thorsten Rose ◽  
Juan Antonio Collado Rojas ◽  
Kurt Appel ◽  
Camille Roesch ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Mode Of Action ◽  
Inflammatory Diseases ◽  
Resistive Pulse ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Pro Inflammatory Cytokines ◽  
Inflammatory Effect

Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are pro-inflammatory cytokines involved in acute and chronic inflammatory diseases. Indeed, immunotherapy blocking these 2 cytokines has been developed. Micro-immunotherapy (MI) also uses ultra-low doses (ULD) of pro-inflammatory cytokines, impregnated on lactose-sucrose pillules, to counteract their overexpression. The study has been conducted with 2 objectives: examine the anti-inflammatory effect in vitro and the capacity of 2 unitary medicines, TNF-α (27 CH) and IL-1β (27 CH), to reduce the secretion of TNF-α in human primary monocytes and THP-1 cells differentiated with phorbol-12-myristate-13-acetate, after lipopolysaccharide (LPS) exposure; then, investigate the presence of particles possibly containing starting materials using tunable resistive pulse sensing technique. The results show that the unitary medicines, tested at 3 pillules concentrations (5.5, 11 and 22 mM), have reduced the secretion of TNF-α in both models by about 10−20% vs. vehicle control, depending on concentration. In this exploratory study, particles (150−1000 nm) have been detected in MI ULD-impregnated pillules and a hypothesis for MI medicines mode of action has been proposed. Conscious that more evaluations are necessary, authors are cautious in the conclusions because the findings described in the study are still limited, and future investigations may lead to different hypothesis.

scholarly journals Soluble CD14 Induces Pro-inflammatory Cytokines in Rheumatoid Arthritis Fibroblast-Like Synovial Cells via Toll-Like Receptor 4

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1689
Author(s):  
Yoshihide Ichise ◽  
Jun Saegusa ◽  
Shino Tanaka-Natsui ◽  
Ikuko Naka ◽  
Shinya Hayashi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Cytokines ◽  
Intercellular Adhesion Molecule ◽  
Toll Like Receptor ◽  
Intercellular Adhesion Molecule 1 ◽  
Toll Like Receptor 4 ◽  
Soluble Cd14 ◽  
Mrna Induction ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Objectives: Synovial fluids of rheumatoid arthritis (RA) patients commonly contain high concentrations of soluble CD14 (sCD14). To investigate its potential role in RA pathogenesis, we tested whether sCD14 binding transmits a signal to fibroblast-like synoviocytes from RA patients (RA-FLS). Methods: The induction of pro-inflammatory cytokines, chemokines, and mediators by sCD14 stimulation of RA-FLS was quantified by real-time PCR and ELISA. Cell proliferation was assessed by the BrdU assay. LPS-RS, a Toll-like receptor 4 (TLR-4) antagonist, was used to block TLR-4 signaling. Results: Soluble CD14 induced the expression of IL-6 mRNA and secretion of the protein. The expression of other pro-inflammatory cytokines and mediators, such as TNF-α, IL-8, intercellular adhesion molecule-1 (ICAM-1), MMP-3, and RANK ligand (RANKL), was also induced by sCD14. In addition, sCD14 stimulation promoted RA-FLS proliferation. LPS-RS abolished IL-6, IL-8, and ICAM-1 mRNA induction by sCD14 in RA-FLS. On the other hand, TNF-α and IL-17A increased TLR-4 expression by RA-FLS and amplified their sCD14-induced IL-6 expression. Conclusions: Soluble CD14 transmits inflammatory signals to RA-FLS via TLR-4. The effects of sCD14 may be augmented in inflammatory milieu. Our results suggest that sCD14 is involved in the pathogenesis of RA and may be a novel therapeutic target.

Pro-inflammatory Cytokines: Cellular and Molecular Drug Targets for Glucocorticoid-induced-osteoporosis via Osteocyte

2018 ◽  
Vol 20 (1) ◽  
pp. 1-15 ◽  
Author(s):  
Tiantian Wang ◽  
Xijie Yu ◽  
Chengqi He
Keyword(s):  
Gap Junctions ◽  
Bone Metabolism ◽  
Inflammatory Cytokines ◽  
Drug Targets ◽  
Bone Mineralization ◽  
Synergistic Effects ◽  
Osteocyte Apoptosis ◽  
Tnf Α ◽  
Factor Α ◽  
Pro Inflammatory Cytokines

Glucocorticoids are widely used to treat varieties of allergic and autoimmune diseases, however, long-term application results in glucocorticoid-induced osteoporosis (GIOP). Inflammatory cytokines: tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) play important regulatory roles in bone metabolism, but their roles in GIOP remain largely unknown. Osteocytes can modulate the formation and function of both osteoblasts and osteoclasts, directly via gap junctions, or indirectly by transferring molecule signaling. Apoptotic osteocytes release RANKL, HMGB1 and pro-inflammatory cytokines to stimulate osteoclastogenesis. Moreover, osteocytes can secrete FGF23 to regulate bone metabolism. Exposure to high levels of GCs can drive osteocyte apoptosis and influence gap junctions, leading to bone loss. GCs treatment is regarded to produce more FGF23 to inhibit bone mineralization. GCs also disrupt the vascular to decrease osteocyte feasibility and mineral appositional rate, resulting in a decline in bone strength. Apoptotic bodies from osteocytes induced by GCs treatment can enhance production of TNF-α and IL-6. On the other hand, TNF-α and IL-6 show synergistic effects by altering osteocytes signaling towards osteoclasts and osteoblasts. In addition, TNF-α can induce osteocyte apoptosis and attribute to a worsened bone quality in GCs. IL-6 and osteocytes may interact with each other. Therefore, we hypothesize that GCs regulate osteocyteogenesis through TNF-α and IL-6, which are highly expressed around osteocyte undergoing apoptosis. In the present review, we summarized the roles of osteocytes in regulating osteoblasts and osteoclasts. Furthermore, the mechanism of GCs altered relationship between osteocytes and osteoblasts/osteoclasts. In addition, we discussed the roles of TNF-α and IL-6 in GIOP by modulating osteocytes. Lastly, we discussed the possibility of using pro-inflammatory signaling pathway as therapeutic targets to develop drugs for GIOP.

scholarly journals Effect of Melittin on Metabolomic Profile and Cytokine Production in PMA-Differentiated THP-1 Cells

Vaccines ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 72 ◽  
Author(s):  
Abdulmalik Alqarni ◽  
Valerie Ferro ◽  
John Parkinson ◽  
Mark Dufton ◽  
David Watson
Keyword(s):  
Inflammatory Cytokines ◽  
Cell Activation ◽  
Flash Chromatography ◽  
System Response ◽  
Macrophage Cell ◽  
Tnf Α ◽  
Immune System Response ◽  
Factor Α ◽  
Necrosis Factor ◽  
Pro Inflammatory Cytokines

Melittin, the major active peptide of honeybee venom (BV), has potential for use in adjuvant immunotherapy. The immune system response to different stimuli depends on the secretion of different metabolites from macrophages. One potent stimulus is lipopolysaccharide (LPS), a component isolated from gram-negative bacteria, which induces the secretion of pro-inflammatory cytokines in macrophage cell cultures. This secretion is amplified when LPS is combined with melittin. In the present study, pure melittin was isolated from whole BV by flash chromatography to obtain pure melittin. The ability of melittin to enhance the release of tumour necrosis factor-α (TNF-α), Interleukin (IL-1β, IL-6, and IL-10) cytokines from a macrophage cell line (THP-1) was then assessed. The response to melittin and LPS, applied alone or in combination, was characterised by metabolic profiling, and the metabolomics results were used to evaluate the potential of melittin as an immune adjuvant therapy. The addition of melittin enhanced the release of inflammatory cytokines induced by LPS. Effective chromatographic separation of metabolites was obtained by liquid chromatography-mass spectrometry (LC-MS) using a ZIC-pHILIC column and an ACE C4 column. The levels of 108 polar and non-polar metabolites were significantly changed (p ˂ 0.05) following cell activation by the combination of LPS and melittin when compared to untreated control cells. Overall, the findings of this study suggested that melittin might have a potential application as a vaccine adjuvant.

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