Inhibitory Effect of Mechanical Load on IL-1 Induced Cartilage Degradation Is Mediated by Interferon-Gamma and IL-1 Receptor 1

2008 ◽  
Author(s):  
C. T. Chen ◽  
S. Park ◽  
M. Bhargava ◽  
P. A. Torzilli
Keyword(s):  
Mechanical Load ◽  
Interleukin 1 ◽  
Cartilage Degradation ◽  
Inhibitory Effect ◽  
Interferon Γ ◽  
Cytokine Signaling ◽  
Matrix Remodeling ◽  
Inhibitory Protein ◽  
Anti Inflammatory ◽  
Related Proteins

Matrix remodeling in articular cartilage is regulated by the elevation and activation of aggrecanases (ADAMTS-4 and ADAMTS-5) and matrix metalloproteinases (MMPs) [2–4, 7–9, 10]. Several recent studies from our and other groups have shown that mechanical loading can counteract interleukin 1 (IL-1) induced pro-inflammatory and catabolic events by down-regulating aggrecanases, MMPs, and pro-inflammatory genes [1, 3, 5, 6], but the molecular mechanism is not clear. Many previous studies have shown that the regulation of pro-inflammatory effect of IL-1 come from several aspects: anti-inflammatory cytokines (TGF-β, IL-10, IL-6 and interferon γ), IL-1 receptor related proteins (IL-1R1, IL-1R2, and IL-1Ra) as well as a family of intracellular inhibitory protein called Suppressor Of Cytokine Signaling (SOCS.) SOCS1 and SOCS3 are especially important, since they can inhibit both MAPK and NF-κB pathways induced by IL-1 [12]. The objective of this study was to determine whether mechanical load affected anti-inflammatory mediators along with anti-catabolic events.

scholarly journals Artemisinin Ameliorates Osteoarthritis by Inhibiting the Wnt/β-Catenin Signaling Pathway

2018 ◽  
Vol 51 (6) ◽  
pp. 2575-2590 ◽  
Author(s):  
Gang Zhong ◽  
Ruiming Liang ◽  
Jun Yao ◽  
Jia Li ◽  
Tongmeng Jiang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cruciate Ligament ◽  
Interleukin 1 ◽  
Cartilage Degradation ◽  
Chondrocyte Apoptosis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cell Viability Assay ◽  
Necrosis Factor Alpha ◽  
Anti Inflammatory

Background/Aims: Current drug therapies for osteoarthritis (OA) are not practical because of the cytotoxicity and severe side-effects associated with most of them. Artemisinin (ART), an antimalarial agent, is well known for its safety and selectivity to kill injured cells. Based on its anti-inflammatory activity and role in the inhibition of OA-associated Wnt/β-catenin signaling pathway, which is crucial in the pathogenesis of OA, we hypothesized that ART might have an effect on OA. Methods: The chondro-protective and antiarthritic effects of ART on interleukin-1-beta (IL-1β)-induced and OA patient-derived chondrocytes were investigated in vitro using cell viability assay, glycosaminoglycan secretion, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and western blotting. We also used OA model rats constructed by anterior cruciate ligament transection and medial meniscus resection (ACLT+MMx) in the joints to investigate the effects of ART on OA by gross observation, morphological staining, immunohistochemistry, and enzyme-linked immunosorbent assay. Results: ART exhibited potent anti-inflammatory effects by inhibiting the expression of proinflammatory chemokines and cytokines, including interleukin (IL)-1β, IL-6, tumor necrosis factor alpha, and matrix metallopeptidase-13. It also showed favorable chondro-protective effect as evidenced by enhanced cell proliferation and viability, increased glycosaminoglycan deposition, prevention of chondrocyte apoptosis, and degeneration of cartilage. Further, ART inhibited OA progression and cartilage degradation via the Wnt/β-catenin signaling pathway, suggesting that it might serve as a Wnt/β-catenin antagonist to reduce inflammation and prevent cartilage degradation. Conclusion: In conclusion, ART alleviates IL-1β-mediated inflammatory response and OA progression by regulating the Wnt/β-catenin signaling pathway. Thereby, it might be developed as a potential therapeutic agent for OA.

Gigantol Alleviates IL-1β-Induced Inflammation and Catabolism in Mouse Osteoarthritis via PI3K/Akt/NF-κB Pathways In Vivo and In Vitro

2021 ◽  
Author(s):  
Gaosheng Zhu ◽  
Keze Miao ◽  
Mingwei Dong ◽  
Jie Cai ◽  
Zhihao Shen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Therapeutic Option ◽  
Interleukin 1 ◽  
Cartilage Degradation ◽  
Research Society ◽  
Necrosis Factor Alpha ◽  
Persistent Inflammation ◽  
Anti Inflammatory

Abstract Osteoarthritis (OA), a prevalent disabling disease, is characterized by irreversible cartilage degradation and persistent inflammation. The etiology as well as pathogenesis of OA are not completely unclear and need further investigation. Gigantol, is a bibenzyl derivative extracted from Dendrobium plants and has been found exhibit multiple effects such as anti-inflammatory effects. Nevertheless, the biological function of gigantol on osteoarthritis (OA) is still uncertain. This study aimed at examining the anti-inflammatory effects and latent mechanisms of gigantol in IL-1β-mediated OA progression. In vitro, we identified that gigantol treatment suppressed tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS) and interleukin-6 (IL-6) in interleukin-1 beta (IL-1β) mediated mouse OA chondrocytes. Gigantol was also shown to dose dependently downregulate the metalloproteinase 13 (MMP13) as well as thrombospondin motifs 5 (ADAMTS5) levels. Moreover, IL-1β-mediated AKT and PI3K phosphorylation as well as NF-κB activation were inhibited by gigantol. Meanwhile, in vivo, we detected that gigantol treatment inhibited degradation of the cartilage degradation and lowered the Osteoarthritis Research Society International scores (OARSI) in OA mouse. Therefore, gigantol is a promising therapeutic option for OA.

scholarly journals Folic Acid Is Able to Polarize the Inflammatory Response in LPS Activated Microglia by Regulating Multiple Signaling Pathways

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Antonia Cianciulli ◽  
Rosaria Salvatore ◽  
Chiara Porro ◽  
Teresa Trotta ◽  
Maria Antonietta Panaro
Keyword(s):  
Folic Acid ◽  
Inflammatory Response ◽  
Signaling Pathways ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Cytokine Signaling ◽  
No Production ◽  
Acid Pretreatment ◽  
Anti Inflammatory ◽  
Multiple Signaling

We investigated the ability of folic acid to modulate the inflammatory responses of LPS activated BV-2 microglia cells and the signal transduction pathways involved. To this aim, the BV-2 cell line was exposed to LPS as a proinflammatory response inducer, in presence or absence of various concentrations of folic acid. The production of nitric oxide (NO) was determined by the Griess test. The levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-10 were determined by ELISA. Inducible NO synthase (iNOS), nuclear transcription factor-kappa B (NF-κB) p65, MAPKs protein, and suppressors of cytokine signaling (SOCS)1 and SOCS3 were analyzed by western blotting. TNF-αand IL-1β, as well as iNOS dependent NO production, resulted significantly inhibited by folic acid pretreatment in LPS-activated BV-2 cells. We also observed that folic acid dose-dependently upregulated both SOCS1 and SOCS3 expression in BV-2 cells, leading to an increased expression of the anti-inflammatory cytokine IL-10. Finally, p-IκBα, which indirectly reflects NF-κB complex activation, and JNK phosphorylation resulted dose-dependently downregulated by folic acid pretreatment of LPS-activated cells, whereas p38 MAPK phosphorylation resulted significantly upregulated by folic acid treatment. Overall, these results demonstrated that folic acid was able to modulate the inflammatory response in microglia cells, shifting proinflammatory versus anti-inflammatory responses through regulating multiple signaling pathways.

Selective inhibition of interleukin-4 gene expression in human T cells by aspirin

Blood ◽  
2001 ◽  
Vol 97 (6) ◽  
pp. 1742-1749 ◽  
Author(s):  
Antonella Cianferoni ◽  
John T. Schroeder ◽  
Jean Kim ◽  
John W. Schmidt ◽  
Lawrence M. Lichtenstein ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Cd4 T Cells ◽  
Inhibitory Effect ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Cytokine Gene Expression ◽  
Cytokine Gene ◽  
Activated T Cells ◽  
Anti Inflammatory

Previous studies indicated that aspirin (acetylsalicylic acid [ASA]) can have profound immunomodulatory effects by regulating cytokine gene expression in several types of cells. This study is the first in which concentrations of ASA in the therapeutic range were found to significantly reduce interleukin (IL)-4 secretion and RNA expression in freshly isolated and mitogen-primed human CD4+ T cells. In contrast, ASA did not affect IL-13, interferon-γ, and IL-2 expression. ASA inhibited IL-4, but not IL-2, promoter-driven chloramphenicol acetyltransferase expression in transiently transfected Jurkat T cells. The structurally unrelated nonsteroidal anti-inflammatory drugs indomethacin and flurbiprofen did not affect cytokine gene expression in T cells, whereas the weak cyclo-oxygenase inhibitor salicylic acid was at least as effective as ASA in inhibiting IL-4 expression and promoter activity. The inhibitory effect of ASA on IL-4 transcription was not mediated by decreased nuclear expression of the known salicylate target nuclear factor (NF)–κB and was accompanied by reduced binding of an inducible factor to an IL-4 promoter region upstream of, but not overlapping, the NF of activated T cells– and NF-κB–binding P1 element. It is concluded that anti-inflammatory salicylates, by means of a previously unrecognized mechanism of action, can influence the nature of adaptive immune responses by selectively inhibiting the expression of IL-4, a critical effector of these responses, in CD4+ T cells.

scholarly journals Amino-alcohol Bio-conjugate of Naproxen Exhibits Anti-inflammatory Activity through NF-κB Signaling Pathway

2020 ◽  
Author(s):  
Mahua Rani Das ◽  
Anindyajit Banerjee ◽  
Sourav Sarkar ◽  
Joydeb Majumder ◽  
Saikat Chakrabarti ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Amino Acid ◽  
Amino Alcohol ◽  
Inhibitory Effect ◽  
Interferon Γ ◽  
Raw 264.7 Cells ◽  
Synthetic Compound ◽  
Inflammatory Drug ◽  
Anti Inflammatory ◽  
Oxide Synthase

AbstractNaproxen sodium (Ns) is a well-known synthetic compound used vastly as a nonsteroidal anti-inflammatory drug (NSAID). Previously, we demonstrated that the hydrogels, made of Ns bio-conjugate (NBC), either with amino alcohol (NBC-1 and 2) or amino acid (NBC-3 and 4), displayed anti-inflammatory properties better than Ns, but the effectiveness was not well explored. Here, we investigated that NBC-2, conjugated with γ-amino alcohol, significantly reduces the expression of pro-inflammatory proteins; such as inducible nitric oxide synthase (iNOS) and cyclooxygenase isoform-2 (COX-2), and the production of pro-inflammatory mediator nitric oxide (NO) in lipopolysaccharide and interferon-γ (LPS/IFN-γ) treated mouse macrophage RAW 264.7 cells, compared with bio-conjugation of β-amino alcohol (NBC-1) or β-amino acid (NBC-3) or α-amino acid NBC (NBC-4). NBC-2 decreases the nuclear localization of transcription factors NF-κB by stabilizing its cytoplasmic functional inhibitor IκBα. Moreover, NBC-2 also displays selective inhibitory effect towards COX-1 enzyme activity as determined by enzymatic assay and in silico molecular docking analysis. Thus, we suggest that NBC-2 may be used as a self-delivery anti-inflammatory drug as compared with other NBCs.TOC Graphic

IFNγ-dependent SOCS3 expression inhibits IL-6-induced STAT3 phosphorylation and differentially affects IL-6 mediated transcriptional responses in endothelial cells

2010 ◽  
Vol 299 (2) ◽  
pp. C354-C362 ◽  
Author(s):  
Hans A. R. Bluyssen ◽  
M. Mehdi Rastmanesh ◽  
Chantal Tilburgs ◽  
Kim Jie ◽  
Sebastiaan Wesseling ◽  
...  
Keyword(s):  
Target Genes ◽  
Interferon Γ ◽  
Cytokine Signaling ◽  
Transcriptional Responses ◽  
Stat3 Phosphorylation ◽  
Socs3 Expression ◽  
Protective Genes ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory ◽  
Interfering Rna

IL-6 has pro- and anti-inflammatory effects and is involved in endothelial cell (EC) dysfunction. The anti-inflammatory effects of IL-6 are mediated by signal transducer and activator of transcription-3 (STAT3), which is importantly controlled by suppressor of cytokine signaling 3 (SOCS3). Therefore, cytokines that modulate SOCS3 expression might inhibit the anti-inflammatory effects of IL-6. We hypothesized that in EC, interferon-γ (IFNγ)-induced SOCS3 expression leads to inhibition of IL-6-induced STAT3 activation and IL-6-dependent expression of anti-, but not pro-inflammatory, target genes. IFNγ activated STAT1 and STAT3 and increased SOCS3 expression in EC. IL-6 only activated STAT3 and induced SOCS3 expression. IFNγ pretreatment of EC inhibited IL-6-induced STAT3 activation accompanied by increased SOCS3 protein. Inhibition of SOCS3 expression, using costimulation, Act-D, and small interfering RNA (siRNA), subsequently implicated the importance of IFNγ-induced SOCS3 in this phenomenon. Pretreatment of EC with IFNγ also affected the transcriptional program induced by IL-6. We identified 1) IL-6 anti-inflammatory target genes that were inhibited by IFNγ, 2) IFNγ-target genes of pro-inflammatory nature that were increased in response to IL-6 in the presence of IFNγ, and 3) a set of target genes that were increased upon IL-6 or IFNγ alone, or combined IFNγ and IL-6. In summary, by increasing SOCS3 expression in EC, IFNγ can selectively inhibit STAT3-dependent IL-6 signaling. This in turn leads to decreased expression of some EC protective genes. In contrast, other genes of pro-inflammatory nature are not inhibited or even increased. This IFNγ-induced shift in IL-6 signaling to a pro-inflammatory phenotype could represent a novel mechanism involved in EC dysfunction.

scholarly journals Spilanthol Inhibits Inflammatory Transcription Factors and iNOS Expression in Macrophages and Exerts Anti-inflammatory Effects in Dermatitis and Pancreatitis

2019 ◽  
Vol 20 (17) ◽  
pp. 4308 ◽  
Author(s):  
Edina Bakondi ◽  
Salam Bhopen Singh ◽  
Zoltán Hajnády ◽  
Máté Nagy-Pénzes ◽  
Zsolt Regdon ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Transcription Factors ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
Interferon Γ ◽  
Inos Expression ◽  
Bioactive Molecules ◽  
Inos Mrna ◽  
No Production ◽  
Anti Inflammatory

Activated macrophages upregulate inducible nitric oxide synthase (iNOS) leading to the profuse production of nitric oxide (NO) and, eventually, tissue damage. Using macrophage NO production as a biochemical marker of inflammation, we tested different parts (flower, leaf, and stem) of the medicinal plant, Spilanthes acmella. We found that extracts prepared from all three parts, especially the flowers, suppressed NO production in RAW macrophages in response to interferon-γ and lipopolysaccharide. Follow up experiments with selected bioactive molecules from the plant (α-amyrin, β-caryophylline, scopoletin, vanillic acid, trans-ferulic acid, and spilanthol) indicated that the N-alkamide, spilanthol, is responsible for the NO-suppressive effects and provides protection from NO-dependent cell death. Spilanthol reduced the expression of iNOS mRNA and protein and, as a possible underlying mechanism, inhibited the activation of several transcription factors (NFκB, ATF4, FOXO1, IRF1, ETS, and AP1) and sensitized cells to downregulation of Smad (TF array experiments). The iNOS inhibitory effect translated into an anti-inflammatory effect, as demonstrated in a phorbol 12-myristate 13-acetate-induced dermatitis and, to a smaller extent, in cerulein-induced pancreatitis. In summary, we demonstrate that spilanthol inhibits iNOS expression, NO production and suppresses inflammatory TFs. These events likely contribute to the observed anti-inflammatory actions of spilanthol in dermatitis and pancreatitis.

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