scholarly journals Low levels of PCSK9 are Associated with Remission in Patients with Rheumatoid Arthritis Treated with Anti- TNF-α: Potential Underlying Mechanisms

2020 ◽  
Author(s):  
Johan Frostegård ◽  
Sabbir Ahmed ◽  
Ingiäld Hafström ◽  
Sofia Ajeganova ◽  
Mizanur Rahman
Keyword(s):  
Rheumatoid Arthritis ◽  
Ldl Receptor ◽  
Etanercept Treatment ◽  
Monocyte Chemoattractant Protein 1 ◽  
Tnf Α ◽  
Immunological Effects ◽  
Low Levels ◽  
Underlying Mechanisms ◽  
One Year

Abstract Background Proprotein convertase subtilisin kexin 9 (PCSK9) targets the LDL-receptor (LDLR) which raises LDL-levels. In addition, PCSK9 has proinflammatory immunological effects. Here we investigate the role of PCSK9 as to the inflammatory activity in patients with rheumatoid arthritis (RA). Methods PCSK9-levels were determined at baseline by ELISA in 160 patients with RA not previously treated with biologics. The patients started anti- TNF-α (adalimumab, infliximab, or etanercept) treatment and were followed up for one year. Disease activity was determined by DAS28. Effects of PCSK9 on cytokine production from macrophages of healthy individuals and synoviocytes from RA patients and inhibition by anti-PCSK9 antibodies were studied in supernatants by ELISA. Results A significantly lower level of PCSK9 at baseline, p=0.035, was observed in patients who reached remission within one year, defined as DAS28<2.6, compared to those not in remission. At 12 months of TNF-α antagonist treatment, the mean DAS28 was reduced but was significantly greater in patients with highest quartile PCSK9 (Q4) compared to those at lowest PCSK9 (Q1) in both crude (p=0.01) and adjusted analysis (p=0.004). In vitro, PCSK9 induced TNF-alpha and IL-1beta in macrophages and monocyte chemoattractant protein-1 (MCP1) in synoviocytes. These effects were inhibited by anti-PCSK9 antibodies. Conclusions Low levels of PCSK9 at baseline is associated with being DAS28-responder to anti-TNF-α treatment in RA. An underlying cause could be that PCSK9 stimulates production of proinflammatory cytokines from macrophages and synoviocytes, effects inhibited by anti-PCSK9 antibodies. PCSK9 could thus play an immunological role in RA.

scholarly journals Low levels of PCSK9 are associated with remission in patients with rheumatoid arthritis treated with anti-TNF-α: potential underlying mechanisms

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Johan Frostegård ◽  
Sabbir Ahmed ◽  
Ingiäld Hafström ◽  
Sofia Ajeganova ◽  
Mizanur Rahman
Keyword(s):  
Rheumatoid Arthritis ◽  
Ldl Receptor ◽  
Etanercept Treatment ◽  
Monocyte Chemoattractant Protein 1 ◽  
Tnf Α ◽  
Immunological Effects ◽  
Previously Treated ◽  
Low Levels ◽  
Underlying Mechanisms

Abstract Background Proprotein convertase subtilisin kexin 9 (PCSK9) targets the LDL-receptor (LDLR) which raises LDL-levels. In addition, PCSK9 has proinflammatory immunological effects. Here, we investigate the role of PCSK9 in relation to the inflammatory activity in patients with rheumatoid arthritis (RA). Methods PCSK9-levels were determined at baseline by ELISA in 160 patients with RA not previously treated with biologics. The patients started anti-TNF-α (adalimumab, infliximab, or etanercept) treatment and were followed-up for 1 year. Disease activity was determined by DAS28. Effects of PCSK9 on cytokine production from macrophages of healthy individuals and synoviocytes from RA patients and inhibition by anti-PCSK9 antibodies were studied in supernatants by ELISA. Results A significantly lower level of PCSK9 at baseline, p = 0.035, was observed in patients who reached remission within 1 year, defined as DAS28 < 2.6, compared to those not in remission. At 12 months of TNF-α antagonist treatment, the mean DAS28 was reduced but was significantly greater in patients with highest quartile PCSK9 (Q4) compared to those at lowest PCSK9 (Q1) in both crude (p = 0.01) and adjusted analysis (p = 0.004). In vitro, PCSK9 induced TNF-alpha and IL-1beta in macrophages and monocyte chemoattractant protein-1 (MCP1) in synoviocytes. These effects were inhibited by anti-PCSK9 antibodies. Conclusions Low levels of PCSK9 at baseline are associated with being DAS28-responder to anti-TNF-α treatment in RA. An underlying cause could be that PCSK9 stimulates the production of proinflammatory cytokines from macrophages and synoviocytes, effects inhibited by anti-PCSK9 antibodies. PCSK9 could thus play an immunological role in RA.

Immuno-compatibility of desaminotyrosine and desaminotyrosyl tyrosine functionalized star-shaped oligo(ethylene glycol)s with different molecular weights

2015 ◽  
Vol 1718 ◽  
pp. 97-102 ◽  
Author(s):  
Toralf Roch ◽  
Konstanze K. Julich-Gruner ◽  
Axel T. Neffe ◽  
Nan Ma ◽  
Andreas Lendlein
Keyword(s):  
Aqueous Solution ◽  
Ethylene Glycol ◽  
Average Molecular Weight ◽  
Molecular Weights ◽  
Immunological Effects ◽  
Microbial Products ◽  
Low Levels ◽  
Chain Lengths ◽  
Immunological Evaluation

ABSTRACTPolymer-based therapeutic strategies require biomaterials with properties and functions tailored to the demands of specific applications leading to an increasing number of newly designed polymers. For the evaluation of those new materials, comprehensive biocompatibility studies including cyto-, tissue-, and immunocompatibility are essential. Recently, it could be demonstrated that star-shaped amino oligo(ethylene glycol)s (sOEG) with a number average molecular weight of 5 kDa and functionalized with the phenol-derived moieties desaminotyrosine (DAT) or desaminotyrosyl tyrosine (DATT) behave in aqueous solution like surfactants without inducing a substantial cytotoxicity, which may qualify them as solubilizer for hydrophobic drugs in aqueous solution. However, for biomedical applications the polymer solutions need to be free of immunogenic contaminations, which could result from inadequate laboratory environment or contaminated starting material. Furthermore, the materials should not induce uncontrolled or undesired immunological effects arising from material intrinsic properties. Therefore, a comprehensive immunological evaluation as perquisite for application of each biomaterial batch is required. This study investigated the immunological properties of sOEG-DAT(T) solutions, which were prepared using sOEG with number average molecular weights of 5 kDa, 10 kDa, and 20 kDa allowing analyzing the influence of the sOEG chain lengths on innate immune mechanisms. A macrophage-based assay was used to first demonstrate that all DAT(T)-sOEG solutions are free of endotoxins and other microbial contaminations such as fungal products. In the next step, the capacity of the different DAT(T)-functionalized sOEG solutions to induce cytokine secretion and generation of reactive oxygen species (ROS) was investigated using whole human blood. It was observed that low levels of the pro-inflammatory cytokines interleukin(IL)-1β and IL-6 were detected for all sOEG solutions but only when used at concentrations above 250 µg·mL-1. Furthermore, only the 20 kDa sOEG-DAT induced low amounts of ROS-producing monocytes. Conclusively, the data indicate that the materials were not contaminated with microbial products and do not induce substantial immunological adverse effectsin vitro,which is a prerequisite for future biological applications.

scholarly journals In vitro evidence for the involvement of H2S pathway in the effect of clodronate during inflammatory response

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rosangela Montanaro ◽  
Alessio D’Addona ◽  
Andrea Izzo ◽  
Carlo Ruosi ◽  
Vincenzo Brancaleone
Keyword(s):  
Inflammatory Markers ◽  
In Vitro Study ◽  
Inos Expression ◽  
Beneficial Effects ◽  
Tnf Α ◽  
Inflammatory State ◽  
Anti Inflammatory ◽  
Underlying Mechanisms ◽  
Inflammatory Effect

AbstractClodronate is a bisphosphonate agent commonly used as anti-osteoporotic drug. Throughout its use, additional anti-inflammatory and analgesic properties have been reported, although the benefits described in the literature could not solely relate to their inhibition of bone resorption. Thus, the purpose of our in vitro study is to investigate whether there are underlying mechanisms explaining the anti-inflammatory effect of clodronate and possibly involving hydrogen sulphide (H2S). Immortalised fibroblast-like synoviocyte cells (K4IM) were cultured and treated with clodronate in presence of TNF-α. Clodronate significantly modulated iNOS expression elicited by TNF-α. Inflammatory markers induced by TNF-α, including IL-1, IL-6, MCP-1 and RANTES, were also suppressed following administration of clodronate. Furthermore, the reduction in enzymatic biosynthesis of CSE-derived H2S, together with the reduction in CSE expression associated with TNF-α treatment, was reverted by clodronate, thus rescuing endogenous H2S pathway activity. Clodronate displays antinflammatory properties through the modulation of H2S pathway and cytokines levels, thus assuring the control of the inflammatory state. Although further investigation is needed to stress out how clodronate exerts its control on H2S pathway, here we showed for the first the involvement of H2S in the additive beneficial effects observed following clodronate therapy.

scholarly journals TheBDKRB2 +9/-9 Polymorphisms Influence Pro-Inflammatory Cytokine Levels in Knee Osteoarthritis by Altering TLR-2 Expression: Clinical and in Vitro Studies

2016 ◽  
Vol 38 (3) ◽  
pp. 1245-1256 ◽  
Author(s):  
Shuo Chen ◽  
Lei Zhang ◽  
Ruonan Xu ◽  
Yunfan Ti ◽  
Yunlong Zhao ◽  
...  
Keyword(s):  
Knee Osteoarthritis ◽  
Inflammatory Cytokine ◽  
Molecular Mechanisms ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mrna Levels ◽  
Knee Oa ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Underlying Mechanisms

Background/Aims: The bradykinin B2 receptor (BDKRB2) +9/-9 gene polymorphisms have been shown to be associated with the susceptibility and severity of osteoarthritis (OA); however, the underlying mechanisms are unclear. In this study, we investigated the correlation between the BDKRB2 +9/-9 polymorphisms and pro-inflammatory cytokine levels in OA and the molecular mechanisms involved. Methods: A total of 156 patients with primary knee OA and 121 healthy controls were enrolled. The BDKRB2 +9/-9 polymorphisms were genotyped. The tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 levels were determined using Enzyme-linked immunosorbent assay (ELISA). The toll-like receptor (TLR)-2 and TLR-4 mRNA levels were determined by quantitative real-time PCR. The basal and bradykinin-stimulated pro-inflammatory cytokine secretion in human OA synoviocytes and the involvement of TLR-2 and mitogen-activated protein kinases (MAPKs) were investigated. Results: The presence of -9 bp genotype is associated with higher TNF-α, IL-6, and IL-8 levels and higher TLR-2 expression in OA patients. The basal and bradykinin-induced TLR-2 expressions in human OA synoviocytes were significantly reduced by specific inhibitors of p38, JNK1/2, and ERK1/2. Both the B2 receptor antagonist MEN16132 and TLR-2 silencing inhibited IL-6 and IL-8 secretion in human OA synoviocytes. Conclusion: The data suggested that the BDKRB2 +9/-9 polymorphisms influence pro-inflammatory cytokine levels in knee osteoarthritis by altering TLR-2 expression.

scholarly journals A Disintegrin and Metalloprotease 15 is Expressed on Rheumatoid Arthritis Synovial Tissue Endothelial Cells and may Mediate Angiogenesis

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 32 ◽  
Author(s):  
Shinichiro Nishimi ◽  
Takeo Isozaki ◽  
Kuninobu Wakabayashi ◽  
Hiroko Takeuchi ◽  
Tsuyoshi Kasama
Keyword(s):  
Rheumatoid Arthritis ◽  
Endothelial Cells ◽  
Conditioned Medium ◽  
Inflammatory Diseases ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Tnf Α ◽  
Adhesion Index

A disintegrin and metalloprotease 15 (ADAM15) is involved in several malignancies. In this study, we investigated the role of ADAM15 in rheumatoid arthritis (RA) angiogenesis. Soluble ADAM15 (s-ADAM15) in serum from RA and normal (NL) subjects was measured using ELISA. To determine membrane-anchored ADAM15 (ADAM15) expression in RA synovial tissues, immunohistochemistry was performed. To examine the role of ADAM15 in angiogenesis, we performed in vitro Matrigel assays and monocyte adhesion assays using human umbilical vein endothelial cells (HUVECs) transfected with ADAM15 siRNA. Finally, to investigate whether angiogenic mediators were affected by ADAM15, cytokines in ADAM15 siRNA-transfected HUVEC-conditioned medium were measured. ADAM15 was significantly higher in RA serum than in NL serum. ADAM15 was also expressed on RAST endothelial cells. ADAM15 siRNA-treated HUVECs had decreased EC tube formation in response to RA synovial fluids compared with non-treated HUVECs. The adhesion index of ADAM15 siRNA-transfected HUVECs was significantly lower than the adhesion index of control siRNA-transfected HUVECs. ENA-78/CXCL5 and ICAM-1 were decreased in tumor necrosis factor (TNF)-α-stimulated ADAM15 siRNA-transfected HUVEC-conditioned medium compared with TNF-α-stimulated control siRNA-transfected HUVEC-conditioned medium. These data show that ADAM15 plays a role in RA angiogenesis, suggesting that ADAM15 might be a potential target in inflammatory diseases such as RA.

Regulating Fibrocartilage Stem Cells via TNF-α/Nf-κB in TMJ Osteoarthritis

2021 ◽  
pp. 002203452110372
Author(s):  
R. Bi ◽  
K. Chen ◽  
Y. Wang ◽  
X. Luo ◽  
Q. Li ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Lineage ◽  
Cartilage Degeneration ◽  
Lineage Tracing ◽  
Sprague Dawley ◽  
Etanercept Treatment ◽  
Tnf Α ◽  
Temporomandibular Joint Osteoarthritis

In this study, we investigate harnessing fibrocartilage stem cell (FCSC) capacities by regulating tumor necrosis factor α (TNF-α) signaling for cartilage repair in temporomandibular joint osteoarthritis (TMJOA). Stem cell specifics for FCSCs were characterized in the presence of TNF-α. Etanercept as a TNF-α inhibitor and BAY 11-7082 as an Nf-κB inhibitor were used to study TNF-α regulation of FCSCs. Lineage tracing was performed in Gli1-CreERT+;Tmfl/fl mice when etanercept (1 mg/kg, every 3 d) or isometric vehicle was subcutaneously injected to trace specific changes in FCSCs. Surgically induced TMJOA Sprague-Dawley rats were generated with BAY 11-7082 (5 mg/kg, every 3 d) or vehicle subcutaneous injection to investigate the functional role of TNF-α/Nf-κB in TMJOA. Anterior disc displacement (ADD) rabbits were used to analyze the therapeutic effect of etanercept as a TMJOA intra-articular treatment with etanercept (0.02 mg in 100 μL, every 2 wk) or isometric vehicle. In vitro, TNF-α inhibited proliferation of FCSCs and increased FCSC apoptosis. TNF-α activation interfered with osteogenic and chondrogenic differentiation of FCSCs, while etanercept could partially recover FCSC specificity from TNF-α. FCSC lineage tracing in Gli1-CreERT+;Tmfl/fl mice showed that the chondrogenic capacity of Gli1+ cell lineage was markedly suppressed in osteoarthritis cartilage, the phenotype of which could be significantly rescued by etanercept. Specifically blocking the Nf-κB pathway could significantly weaken the regulatory effect of TNF-α on FCSC specificity in vitro and in TMJOA rats in vivo. Finally, intra-articular etanercept treatment efficiently rescued TMJ cartilage degeneration and growth retardation in ADD rabbits. Inhibition of TNF-α signaling reduced Nf-κB transcripts and recovered FCSC specificities. In vivo, etanercept treatment effectively rescued the osteoarthritis phenotype in TMJOA mice and ADD rabbits. These data suggest a novel therapeutic mechanism whereby TNF-α/Nf-κB inhibition promotes FCSC chondrogenic capacity for cartilage transformation in TMJOA.

Mesenchymal Stem Cells Convert Human Macrophages to a Novel Type of Alternatively Activated Macrophages.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3632-3632 ◽  
Author(s):  
Jaehyup Kim ◽  
Peiman Hematti
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Cell Surface ◽  
Activated Macrophages ◽  
Alternatively Activated Macrophages ◽  
Tnf Α ◽  
Low Levels ◽  
Alternatively Activated

Abstract Abstract 3632 Poster Board III-568 Mesenchymal stem cells (MSCs) are capable of modulating the immune system through interaction with a wide range of immune cells. This study investigates the hypothesis that interaction of MSCs with macrophages could play a significant role in their anti-inflammatory/immune modulatory effects. All studies were approved by IRB of University of Wisconsin School of Medicine and Public Health. MSCs were culture expanded from discarded bone marrow filters after bone marrow harvest from normal healthy sibling HLA-matched donors. We used passages -35 for our experiments. Ex vivo culture expanded MSCs were characterized by their cell surface phenotype (positive for MSC markers: CD29, CD44, CD73, CD90, and CD105; and negative for hematopoietic markers: CD31, CD34, and CD45), and their differentiation potential into bone, fat and cartilage. Monocytes were isolated from peripheral blood mononuclear cell fraction of healthy donors using CD14+ Miltenyi magnetic bead cell separation method. We cultured human CD14+ monocytes for seven days without any added cytokines to generate macrophages, and then co-cultured them for three more days with culture-expanded MSCs. We used cell surface antigen expression and intracellular cytokine expression patterns to study the immunophenotype of macrophages at the end of this co-culture period, and phagocytic assays to investigate their functional activity in vitro. Macrophages co-cultured with MSCs consistently showed high level expression of CD206, a marker of alternatively activated macrophages, in addition to being positive fro CD14 marker. Using CD1a and CD209 staining we did not detect presence of any dendritic cells either at the end of seven days culture of monocyte-derived macrophages or at the end of co-culture period. Furthermore, macrophages that were co-cultured with MSCs expressed high levels of IL-10 and low levels of IL-12, as determined by intracellular staining, typical of alternatively activated macrophages. However, macrophages co-cultured with MSCs also expressed high levels of IL-6 and low levels of TNF-α, compared to controls. Functionally, macrophages co-cultured with MSCs showed a higher level of phagocytic activity using Alexa 488-conjugated E. coli phagocytic assay. In summary we describe a novel type of human macrophage generated in vitro after co-culture with MSCs that assume an immunophenotype defined as IL-10 high, IL-12 low, IL-6 high and TNF-α low secreting cells. These MSC-educated macrophages may be a unique and novel type of alternatively activated macrophages with potentially significant role in tissue repair. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Left ventricular function in rheumatoid arthritis during anti-TNF-α treatment: a speckle tracking prospective echocardiographic study

2016 ◽  
Vol 84 (1-2) ◽  
Author(s):  
Enrico Vizzardi ◽  
Ilaria Cavazzana ◽  
Franco Franceschini ◽  
Ivano Bonadei ◽  
Edoardo Sciatti ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Heart Failure ◽  
Speckle Tracking ◽  
Longitudinal Strain ◽  
Systolic Function ◽  
Global Longitudinal Strain ◽  
Left Ventricular ◽  
Cardiac Complications ◽  
Tnf Α ◽  
One Year

<p><strong>Aim</strong>. Rheumatoid arthritis (RA) shows a high risk for cardiovascular disease, including heart failure. Although TNF-α has been implicated in the pathogenesis of myocardial remodelling, TNF-α inhibition did not show any efficacy in patients with advanced heart failure and should be contraindicated in RA with cardiac complications. We aimed to assess global left ventricular (LV) systolic function using global longitudinal strain (GLS) as a measure of myocardial deformation, in a group of RA patients before and during anti-TNF-α treatment. <strong>Methods</strong>. 13 patients (female:male 7:6) affected by RA were prospectively followed for one year during anti TNF-α treatment. Every subject underwent echocardiography before starting anti-TNF-α drugs and after one year of treatment, to evaluate LV ejection fraction (EF), telediastolic diameter, telediastolic volume and global longitudinal strain (GLS) that was calculated using 2D speckle tracking as the mean GLS from three standard apical views (2, 3 and 4 -chambers). The patients showed a mean age of 43 years at RA onset (SD: 13) and a mean follow-up of 7.3 years (SD: 4.8). Steroid and methotrexate were used in 84.6% and 100%, respectively, in association with etanercept (6 cases), adalimumab (4 cases) and infliximab (3 cases). <strong>Results</strong>. Patients globally showed a normal EF before and after one year of treatment (mean: 65% and 65.7%, respectively). GLS did not differ before or after anti-TNF-α treatment (mean: -15.8% and -16.7%, respectively). <strong>Conclusion</strong>. Anti-TNF-α treatment did not significantly modify myocardial contractility after 12 months.</p><p> </p><p> </p>

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