scholarly journals Essential Role for the C5a Receptor in Regulating the Effector Phase of Synovial Infiltration and Joint Destruction in Experimental Arthritis

2002 ◽  
Vol 196 (11) ◽  
pp. 1461-1471 ◽  
Author(s):  
Ethan P. Grant ◽  
Dominic Picarella ◽  
Timothy Burwell ◽  
Tracy Delaney ◽  
Alisa Croci ◽  
...  
Keyword(s):  
Synovial Fluid ◽  
Joint Destruction ◽  
Inflammatory Cells ◽  
Receptor Expression ◽  
C5a Receptor ◽  
Genetic Ablation ◽  
Proinflammatory Mediators ◽  
Related Family ◽  
Factor Α ◽  
Necrosis Factor

A characteristic feature of rheumatoid arthritis is the abundance of inflammatory cells in the diseased joint. Two major components of this infiltrate are neutrophils in the synovial fluid and macrophages in the synovial tissue. These cells produce cytokines including tumor necrosis factor α and other proinflammatory mediators that likely drive the disease through its effector phases. To investigate what mechanisms underlie the recruitment of these cells into the synovial fluid and tissue, we performed expression analyses of chemoattractant receptors in a related family that includes the anaphylatoxin receptors and the formyl-MetLeuPhe receptor. We then examined the effect of targeted disruption of two abundantly expressed chemoattractant receptors, the receptors for C3a and C5a, on arthritogenesis in a mouse model of disease. We report that genetic ablation of C5a receptor expression completely protects mice from arthritis.

scholarly journals TNF is a homoeostatic regulator of distinct epigenetically primed human osteoclast precursors

2021 ◽  
pp. annrheumdis-2020-219262
Author(s):  
Cecilia Ansalone ◽  
John Cole ◽  
Sabarinadh Chilaka ◽  
Flavia Sunzini ◽  
Shatakshi Sood ◽  
...  
Keyword(s):  
Epigenetic Modification ◽  
Human Peripheral Blood ◽  
Joint Destruction ◽  
Receptor Expression ◽  
Skeletal Health ◽  
Flow Cytometric ◽  
Human Osteoclast ◽  
The Relationship ◽  
Pathological Consequence ◽  
Necrosis Factor

ObjectivesCirculating myeloid precursors are responsible for post-natal osteoclast (OC) differentiation and skeletal health, although the exact human precursors have not been defined. Enhanced osteoclastogenesis contributes to joint destruction in rheumatoid arthritis (RA) and tumour necrosis factor (TNF) is a well-known pro-osteoclastogenic factor. Herein, we investigated the interplay between receptor activator of nuclear factor kappa-Β ligand (RANK-L), indispensable for fusion of myeloid precursors and the normal development of OCs, and TNF in directing the differentiation of diverse pre-OC populations derived from human peripheral blood.MethodsFlow cytometric cell sorting and analysis was used to assess the potential of myeloid populations to differentiate into OCs. Transcriptomic, epigenetic analysis, receptor expression and inhibitor experiments were used to unravel RANK-L and TNF signalling hierarchy.ResultsTNF can act as a critical homoeostatic regulator of CD14+ monocyte (MO) differentiation into OCs by inhibiting osteoclastogenesis to favour macrophage development. In contrast, a distinct previously unidentified CD14−CD16−CD11c+ myeloid pre-OC population was exempt from this negative regulation. In healthy CD14+ MOs, TNF drove epigenetic modification of the RANK promoter via a TNFR1-IKKβ-dependent pathway and halted osteoclastogenesis. In a subset of patients with RA, CD14+ MOs exhibited an altered epigenetic state that resulted in dysregulated TNF-mediated OC homoeostasis.ConclusionsThese findings fundamentally re-define the relationship between RANK-L and TNF. Moreover, they have identified a novel pool of human circulating non-MO OC precursors that unlike MOs are epigenetically preconditioned to ignore TNF-mediated signalling. In RA, this epigenetic preconditioning occurs in the MO compartment providing a pathological consequence of failure of this pathway.

Tumor necrosis factor-α inhibitors alleviation of experimentally induced neuropathic pain is associated with modulation of TNF receptor expression

2014 ◽  
Vol 92 (11) ◽  
pp. 1490-1498 ◽  
Author(s):  
Pablo Andrade ◽  
Govert Hoogland ◽  
John S. Del Rosario ◽  
Harry W. Steinbusch ◽  
Veerle Visser-Vandewalle ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Receptor Expression ◽  
Tnf Receptor ◽  
Factor Α ◽  
Necrosis Factor ◽  
Experimentally Induced

Pulmonary-specific expression of tumor necrosis factor-α alters surfactant lipid metabolism

2002 ◽  
Vol 282 (4) ◽  
pp. L735-L742 ◽  
Author(s):  
James L. Carroll ◽  
Diann M. McCoy ◽  
Stephen E. McGowan ◽  
Ronald G. Salome ◽  
Alan J. Ryan ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Transgenic Mice ◽  
Tumor Necrosis ◽  
Inflammatory Cells ◽  
Specific Expression ◽  
Tnf Α ◽  
Surfactant Secretion ◽  
Surfactant Lipid ◽  
Factor Α ◽  
Necrosis Factor

Tumor necrosis factor (TNF)-α is a major cytokine implicated in inducing acute and chronic lung injury, conditions associated with surfactant phosphatidylcholine (PtdCho) deficiency. Acutely, TNF-α decreases PtdCho synthesis but stimulates surfactant secretion. To investigate chronic effects of TNF-α, we investigated PtdCho metabolism in a murine transgenic model exhibiting lung-specific TNF-α overexpression. Compared with controls, TNF-α transgenic mice exhibited a discordant pattern of PtdCho metabolism, with a decrease in PtdCho and disaturated PtdCho (DSPtdCho) content in the lung, but increased levels in alveolar lavage. Transgenics had lower activities and increased immunoreactive levels of cytidylyltransferase (CCT), a key PtdCho biosynthetic enzyme. Ceramide, a CCT inhibitor, was elevated, and linoleic acid, a CCT activator, was decreased in transgenics. Radiolabeling studies revealed that alveolar reuptake of DSPtdCho was significantly decreased in transgenic mice. These observations suggest that chronic expression of TNF-α results in a complex pattern of PtdCho metabolism where elevated lavage PtdCho may originate from alveolar inflammatory cells, decreased surfactant reuptake, or altered surfactant secretion. Reduced parenchymal PtdCho synthesis appears to be attributed to CCT enzyme that is physiologically inactivated by ceramide or by diminished availability of activating lipids.

scholarly journals Procalcitonin and Proinflammatory Cytokine Clearance during Continuous Venovenous Haemofiltration in Septic Patients

2002 ◽  
Vol 30 (3) ◽  
pp. 269-274 ◽  
Author(s):  
A. A. Dahaba ◽  
G. A. Elawady ◽  
P. H. Rehak ◽  
W. F. List
Keyword(s):  
Proinflammatory Cytokine ◽  
Tumour Necrosis ◽  
Prognostic Markers ◽  
Plasma Concentrations ◽  
Tumour Necrosis Factor Α ◽  
Proinflammatory Mediators ◽  
Continuous Venovenous Haemofiltration ◽  
The Mean ◽  
Factor Α ◽  
Necrosis Factor

Procalcitonin (PCT), interleukin-6 (IL-6), tumour necrosis factor α (TNFα), and interleukin-1β (IL-1β) are important clinical prognostic markers in ICU septic patients. The goal of the study was to determine whether continuous venovenous haemofiltration (CVVH), using an AN69 haemofilter, leads to elimination of PCT, TNFα, IL-6 and IL-1βin 13 septic patients with multi-organ failure. At the start of haemofiltration (0), 6 and 12 hours the mean afferent plasma concentration ±SD of PCT (10.1±9.1, 7±6, 5.9±5.7 ng/ml), IL-6 (804.6±847.6, 611.7±528.4, 575.2±539.2 pg/ml), and that of TNFα (4.5±2.6, 4±3.1, 3.8±2.9 pg/ml) significantly declined during CVVH. The efferent plasma concentrations were significantly lower than the corresponding afferent concentrations. PCT, IL-6 and TNFαwere detectable in the ultra-filtrate of all patients. IL-1βwas only detectable in the plasma of eight patients and the ultrafiltrate of five patients. The plasma clearance of PCT, IL-6 and TNFαsignificantly decreased after 12 hours as a result of a decline in the adsorptive elimination of the mediators due to progressive membrane saturation. We demonstrated that if PCT, IL-6 and TNFα are used as clinical prognostic markers in septic patients who are treated with CVVH using an AN69 membrane, one should be aware that their plasma level could be modified by the therapy. In addition CVVH could represent an appropriate tool to remove a broad spectrum of proinflammatory mediators, if such removal is required in septic patients.

Effect of endothelin antagonism on the production of cytokines in eosinophilic airway inflammation

2001 ◽  
Vol 280 (4) ◽  
pp. L659-L665 ◽  
Author(s):  
Finn Finsnes ◽  
Torstein Lyberg ◽  
Geir Christensen ◽  
Ole H. Skjønsberg
Keyword(s):  
Tumor Necrosis Factor ◽  
Airway Inflammation ◽  
Bronchial Asthma ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Mrna Level ◽  
Mrna Levels ◽  
Proinflammatory Mediators ◽  
Factor Α ◽  
Necrosis Factor

Endothelin (ET)-1 has been launched as an important mediator in bronchial asthma, which is an eosinophilic airway inflammation. However, the interplay between ET-1 and other proinflammatory mediators during the development of airway inflammation has not been elucidated. We wanted to study 1) whether the production of ET-1 precedes the production of other proinflammatory mediators and 2) whether ET-1 stimulates the production of these mediators within the airways. These hypotheses were studied during the development of an eosinophilic airway inflammation in rats. The increase in ET-1 mRNA level in lung tissue preceded the increase in mRNA levels of tumor necrosis factor-α, interleukin (IL)-1β, and IL-8. Treatment of the animals with the ET receptor antagonist bosentan resulted in a substantial decrease in the concentrations of tumor necrosis factor-α, IL-4, IL-1β, interferon-γ, and ET-1 in bronchoalveolar lavage fluid. In conclusion, the synthesis of ET-1 as measured by increased mRNA level precedes the synthesis of other proinflammatory cytokines of importance for the development of an eosinophilic airway inflammation, and ET antagonism inhibits the production of these mediators within the airways. Whether treatment with ET antagonists will prove beneficial for patients with eosinophilic airway inflammations like bronchial asthma is not yet known.

scholarly journals Synovial Fluid Profile at the Time of Anterior Cruciate Ligament Reconstruction and Its Association With Cartilage Matrix Composition 3 Years After Surgery

2018 ◽  
Vol 46 (4) ◽  
pp. 890-899 ◽  
Author(s):  
Keiko Amano ◽  
Janet L. Huebner ◽  
Thomas V. Stabler ◽  
Matthew Tanaka ◽  
Charles E. McCulloch ◽  
...  
Keyword(s):  
Anterior Cruciate Ligament ◽  
Synovial Fluid ◽  
Ligament Reconstruction ◽  
Cruciate Ligament ◽  
Matrix Composition ◽  
Sulfated Glycosaminoglycan ◽  
Anterior Cruciate ◽  
Factor Α ◽  
Necrosis Factor ◽  
And Cartilage

Background: Anterior cruciate ligament tears can lead to posttraumatic osteoarthritis. In addition to biomechanical factors, changes in biochemical profiles within the knee joint after injury and anterior cruciate ligament reconstruction (ACLR) may play a role in accelerating joint degeneration. Hypothesis/Purpose: It was hypothesized that cartilage matrix composition after ACLR is associated with the degree of inflammatory response after initial injury. This study evaluated the association between the inflammatory response after injury—as indicated by cytokine, metalloproteinase, and cartilage degradation marker concentrations in synovial fluid—and articular cartilage degeneration, measured by T1ρ and T2 quantitative magnetic resonance imaging up to 3 years after ACLR. Study Design: Cohort study; Level of evidence, 2. Methods: Twenty-six subjects from a longitudinal cohort study who underwent ACLR at a mean 8.5 weeks after injury (range, 4-19 weeks) had synovial fluid aspirated at the time of surgery. Immunoassays quantified biomarkers in synovial fluid. T1ρ and T2 values of articular cartilage were calculated with magnetic resonance scans acquired prior to surgery and at 6 months and 1, 2, and 3 years after surgery. Pearson correlation coefficients were calculated among the various biomarkers. K-means clustering was used to group subjects with similar biomarker profiles. Generalized estimating equations were used to find the overall differences in T1ρ and T2 values throughout these first 3 years after surgery between the clusters while controlling for other factors. Results: Significant and strong correlations were observed between several cytokines (interleukin 6 [IL-6], IL-8, IL-10, and tumor necrosis factor α) and 2 matrix metalloproteinases (MMP-1 and MMP-3) ( P < .05). Moderate correlations were found among combinations of C-terminal crosslinked telopeptide type II collagen, N-terminal telopeptide, cartilage oligomeric matrix protein, and sulfated glycosaminoglycan ( P < .05). Two clusters were generated, 1 of which was characterized by lower concentrations of cytokines (IL-6, IL-8, IL-10, tumor necrosis factor α) and MMP-1 and MMP-3 and higher sulfated glycosaminoglycan. This cluster was associated with significantly higher T1ρ and T2 values in the medial tibial and patellar cartilage over the first 3 years after ACLR. Conclusion: At the time of ACLR surgery, profiles of synovial fluid inflammatory cytokines, degradative enzymes, and cartilage breakdown products show promise as predictors of abnormal cartilage tissue integrity (increased T1ρ and T2 values) throughout the first 3 years after surgery. Clinical Relevance: The results suggest an intricate relationship between inflammation and cartilage turnover, which can in turn be influenced by timing after injury and patient factors.

scholarly journals Short-term alpha- or gamma-delta-enriched tocopherol oil supplementation differentially affects the expression of proinflammatory mediators: selective impacts on characteristics of protein tyrosine nitration in vivo

2013 ◽  
Vol 3 (1) ◽  
pp. 6 ◽  
Author(s):  
Ted H. Elsasser ◽  
Stanislaw Kahl ◽  
Katie M. Lebold ◽  
Maret G. Traber ◽  
Jessica Shaffer ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Short Term ◽  
Proinflammatory Response ◽  
E Coli ◽  
Amyloid A ◽  
Proinflammatory Mediators ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

While vitamin E has been used for decades in cattle diets, the principle form used traditionally is the synthetic α-isoform acetate or succinate and largely no data exist on the biological partitioning or functionality of the major naturally occurring γ- and δ-isoforms in cattle. Using tyrosine 3’-nitrated protein (pNT) as a biomarker of nitrosative cell stress, we sought to evaluate the effectiveness of short-term feeding supplementation of high content natural α-tocopherol (<em>α-T</em>, 96% α-isomer) compared to high content γ- and δ-enriched low α-content mixed tocopherol oils (<em>γ-T</em>, ~70% <em>γ-</em>, 20% δ-, &lt;5% α-isoform) to mitigate systemic and hepatic aspects of the proinflammatory response to endotoxin (LPS). Calves fed diets supplemented with <em>α-T</em>, <em>γ-T</em> for five days or no tocopherol supplement (<em>T0E</em>) were challenged with a low-level of LPS (0.25 μg/kg, iv, <em>E. coli </em>055:B5) sufficient to effect a liver nitration response. As fed,<em> α-T</em> or <em>γ-T</em> increased plasma and liver content of the respective tocopherols reflecting their relative abundance in the respective diets. Plasma or tissue mediators and biomarkers of the proinflammatory response [plasma concentrations of tumor necrosis factor-α (TNF-α, P&lt;0.001), nitrate+nitrite (NOx, P&lt;0.01), and serum amyloid A (SAA, P&lt;0.001)], and general liver content of pNT (P&lt;0.005) increased after LPS. LPS-mediated increases in TNF-α were not dif- ferent between diet treatments; both plasma NOx (P&lt;0.05) and generalized liver pNT (P&lt;0.03) responses were attenuated significantly in <em>α-T </em>and <em>γ-T versus T0E calves</em>. Plasma SAA was significantly decreased in γ-T calves at 24 h post-LPS relative to responses in <em>α-T</em> or <em>T0E </em>calves. The nitration of the mitochondrial proteins 24 h post-LPS was not only attenuated in <em>α-T</em> and <em>γ-T vs T0E</em>, but also the mitigating effect of <em>γ-T</em> on these specific nitration events was greater than that of <em>α-T </em>(P&lt;0.01). Results are consistent with the concept that short-term <em>α-T</em> or <em>γ-T</em> supplementation can effectively decrease proinflammatory liver pNT after LPS; some mitochondrial nitration targets may be better protected with prophylactic supplementation with γ-,δ-tocopherol enriched oil.

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