scholarly journals Monocyte TREM-1 Levels Associate With Anti-TNF Responsiveness in IBD Through Autophagy and Fcγ-Receptor Signaling Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Marileen M. Prins ◽  
Bram Verstockt ◽  
Marc Ferrante ◽  
Séverine Vermeire ◽  
Manon E. Wildenberg ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Predictive Marker ◽  
High Expression ◽  
Fcγ Receptor ◽  
Expression Levels ◽  
Tnf Α ◽  
Expression Activity ◽  
Inflammatory Bowel ◽  
Autophagy Pathway ◽  
Necrosis Factor

The expression of Triggering Receptor Expressed on Myeloid cells (TREM)-1 has been described as a predictive marker for anti-Tumor Necrosis Factor (TNF)-α monoclonal antibody (mAb) therapy responsiveness in patients with inflammatory bowel disease (IBD). Here we investigated expression of TREM-1 specifically in CD14+ monocytes in relation to anti-TNF response. The pretreatment TREM-1 expression levels of CD14+ monocytes of Crohn’s disease (CD) patients were predictive of outcome to anti-TNF mAb therapy, with low TREM-1 expression associated with response to anti-TNF. FACSorting of CD14+ monocytes with different TREM-1 levels showed that differentiation towards regulatory CD206+ M2 type macrophages by anti-TNF was suppressed in CD14+ monocytes with high TREM-1 expression. Activity of the Fcγ-Receptor and autophagy pathway, both necessary for M2 type differentiation and the response to anti-TNF, were decreased in CD14+ monocytes with high expression of TREM-1. We confirmed that the activity of the Fcγ-Receptor pathway was decreased in the CD patients that did not respond to anti-TNF therapy and that it was negatively correlated with TREM-1 expression levels in the CD patient cohort. In conclusion, our results indicate that TREM-1 expression levels in CD14+ monocytes associate with decreased autophagy and FcγR activity resulting in decreased differentiation to M2 type regulatory macrophages upon anti-TNF mAb treatment, which may explain anti-TNF non-response in IBD patients with high expression levels of TREM-1.

scholarly journals Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease

Pharmaceutics ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 539
Author(s):  
Bahez Gareb ◽  
Antonius T. Otten ◽  
Henderik W. Frijlink ◽  
Gerard Dijkstra ◽  
Jos G. W. Kosterink
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Genetically Modified Organisms ◽  
Intestinal Inflammation ◽  
Systemic Exposure ◽  
Tnf Α ◽  
Inflammatory Bowel ◽  
Factor Α ◽  
Necrosis Factor

Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by intestinal inflammation. Increased intestinal levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) are associated with disease activity and severity. Anti-TNF-α therapy is administered systemically and efficacious in the treatment of IBD. However, systemic exposure is associated with adverse events that may impede therapeutic treatment. Clinical studies show that the efficacy correlates with immunological effects localized in the gastrointestinal tract (GIT) as opposed to systemic effects. These data suggest that site-specific TNF-α inhibition in IBD may be efficacious with fewer expected side effects related to systemic exposure. We therefore reviewed the available literature that investigated the efficacy or feasibility of local TNF-α inhibition in IBD. A literature search was performed on PubMed with given search terms and strategy. Of 8739 hits, 48 citations were included in this review. These studies ranged from animal studies to randomized placebo-controlled clinical trials. In these studies, local anti-TNF-α therapy was achieved with antibodies, antisense oligonucleotides (ASO), small interfering RNA (siRNA), microRNA (miRNA) and genetically modified organisms. This narrative review summarizes and discusses these approaches in view of the clinical relevance of local TNF-α inhibition in IBD.

scholarly journals Evidence that Tristetraprolin Binds to AU-Rich Elements and Promotes the Deadenylation and Destabilization of Tumor Necrosis Factor Alpha mRNA

1999 ◽  
Vol 19 (6) ◽  
pp. 4311-4323 ◽  
Author(s):  
Wi S. Lai ◽  
Ester Carballo ◽  
Julie R. Strum ◽  
Elizabeth A. Kennington ◽  
Ruth S. Phillips ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Zinc Finger ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Intact Cells ◽  
Expression Levels ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Mice deficient in tristetraprolin (TTP), the prototype of a family of CCCH zinc finger proteins, develop an inflammatory syndrome mediated by excess tumor necrosis factor alpha (TNF-α). Macrophages derived from these mice oversecrete TNF-α, by a mechanism that involves stabilization of TNF-α mRNA, and TTP can bind directly to the AU-rich element (ARE) in TNF-α mRNA (E. Carballo, W. S. Lai, and P. J. Blackshear, Science 281:1001–1005, 1998). We show here that TTP binding to the TNF-α ARE is dependent upon the integrity of both zinc fingers, since mutation of a single cysteine residue in either zinc finger to arginine severely attenuated the binding of TTP to the TNF-α ARE. In intact cells, TTP at low expression levels promoted a decrease in size of the TNF-α mRNA as well as a decrease in its amount; at higher expression levels, the shift to a smaller TNF-α mRNA size persisted, while the accumulation of this smaller species increased. RNase H experiments indicated that the shift to a smaller size was due to TTP-promoted deadenylation of TNF-α mRNA. This CCCH protein is likely to be important in the deadenylation and degradation of TNF-α mRNA and perhaps other ARE-containing mRNAs, both in normal physiology and in certain pathological conditions.

Effectiveness of tumor necrosis factor α inhibitors and their concentration and immunogenicity: features in various immune-mediated diseases

2021 ◽  
pp. 47-52
Author(s):  
T. Yu. Nuriakhmetova ◽  
I. Kh. Valeeva ◽  
Ya. O. Shevnina ◽  
N. A. Cheremina ◽  
E. V. Sukhorukova ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Certolizumab Pegol ◽  
Low Concentration ◽  
Immune Mediated ◽  
Tnf Α ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Factor Α ◽  
Necrosis Factor

Aim. To compare the concentration and immunogenicity of TNF-α inhibitors (TNFi) and their relationship with efficacy in patients with rheumatic diseases (RD) and inflammatory bowel diseases (IBD).Materials and methods. The study included 104 patients with RD (48.1%) and IBD (51.9%) who received infliximab (INF, 30.8%), adalimumab (ADA, 38.5%) and certolizumab pegol (CZP, 30.8%). We assessed the efficacy of the drug, trough concentration of TNFi and the level of antibodies. In 30 patients, the concentration of TNFi and the level of antibodies were assessed twice with an interval of 15 [13; 17] months.Results. TNF-α inhibitors were effective in 77 (74%) patients. In the group of IBD and RD, the incidence of inefficiency was 33.3% and 18.0%, the ineffectiveness of CZP was found only in IBD group (p = 0.024). A low concentration of TNFi was detected at the first visit in 29 (53.7%) patients with IBD and 24 (48.0%) with RD, at the second visit in 4 (36.4%) patients with IBD and 9 (47.4%) with RD. In all patients with RD who did not respond to IFN and CZP, the subtherapeutic concentration was determined (p = 0.047), in the IBD group – only in 64.3% cases (p > 0.050). At the first visit, antibodies to TNFi were found in 24 (23.1%) patients, at the second visit in 7 (23.3%) exclusively in the RD group (p = 0.019), in 5 of them repeatedly. The formation of Ab was associated with 27.8% of cases of escape of the effect of TNF-α in IBD and 22.2% of cases of ineffectiveness in RD (p > 0.050).Conclusions. The incidence of TNF-α efficacy did not differ between RD and IBD, CZP ineffectiveness was observed exclusively in patients with IBD. In patients with RD, a significant relationship was found between ineffectiveness and low concentration of TNFi. The frequency of Ab formation did not differ between the groups of diseases.

scholarly journals Tumor Necrosis Factor-α in Serum of Patients with Inflammatory Bowel Disease as Measured by a Highly Sensitive Immuno-PCR

2001 ◽  
Vol 47 (7) ◽  
pp. 1297-1301 ◽  
Author(s):  
Momoko Komatsu ◽  
Daisuke Kobayashi ◽  
Kaori Saito ◽  
Daisuke Furuya ◽  
Atsuhito Yagihashi ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Pcr Amplification ◽  
Median Serum ◽  
Tnf Α ◽  
Inflammatory Bowel ◽  
Factor Α ◽  
Necrosis Factor

Abstract Background: The significance of serum concentrations of tumor necrosis factor-α (TNF-α) in the pathogenesis of inflammatory bowel disease (IBD) is uncertain. We measured TNF-α in serum from IBD patients by immuno-PCR to analyze the relationship between TNF-α and pathophysiologic state in IBD. Methods: Serum samples were collected from 54 healthy blood donors, 29 patients with ulcerative colitis (UC; 46 samples), and 7 patients with Crohn disease (CD; 8 samples). DNA label was generated by PCR amplification using biotinylated primer and was bound with streptavidin to biotinylated third antibody. TNF-α sandwiched by antibodies was detected by PCR amplification of the DNA label. Results: TNF-α could be measured in all samples. The median serum concentration in IBD patients overall was ∼390-fold higher than in healthy donors (median increase, 380-fold for UC, 640-fold for CD). The median serum TNF-α concentration was 1.7-fold higher in the active stage of UC than in the inactive stage (P <0.05), and this difference could be detected in individual patients. Conclusions: Sensitive measurement of serum TNF-α could provide an important pathophysiologic marker for the presence and activity of IBD.

Comparative Analysis of the 3-Year Persistence Rate with Second-Line Vedolizumab and Tumor Necrosis Factor-α Inhibitors in Patients with Inflammatory Bowel Disease Followed in Gastroenterology Practices in Germany

2020 ◽  
Vol 38 (6) ◽  
pp. 466-473
Author(s):  
Ulf Helwig ◽  
Fiona Braegger ◽  
Karel Kostev ◽  
Carsten Schmidt
Keyword(s):  
Tumor Necrosis ◽  
Matched Pair ◽  
Second Line ◽  
Matched Pair Analysis ◽  
Therapy Initiation ◽  
Tnf Α ◽  
Inflammatory Bowel ◽  
Factor Α ◽  
Pair Analysis ◽  
Necrosis Factor

<b><i>Background:</i></b> Our goal was to investigate the 3-year persistence rates with second-line vedolizumab and tumor necrosis factor-α (TNF-α) inhibitors (i.e., adalimumab, golimumab, infliximab) in patients with inflammatory bowel disease (IBD) who were followed in gastroenterology practices in Germany. <b><i>Methods:</i></b> This study included patients aged ≥18 years who had received prescriptions for second-line biological drugs in Germany between 2014 and 2017 (<i>n</i> = 5,150) retrieved from the longitudinal prescription database. Vedolizumab users were matched to adalimumab, golimumab, and infliximab users based on age, sex, and index year. The primary outcome of the study was the rate of persistence with vedolizumab compared with the rate of persistence with adalimumab, golimumab, and infliximab within 3 years of second-line therapy initiation in IBD patients. Persistence was estimated as therapy time without discontinuation, with discontinuation being defined as at least 90 days without any prescription for the biological drug of interest. <b><i>Results:</i></b> After matching patients who had received vedolizumab with those who had received adalimumab, the rate of persistence after 3 therapy years was 30.3% for vedolizumab and 27.9% for adalimumab (log-rank <i>p</i> = 0.005). The corresponding figures were 27.8 and 20.8% in the vedolizumab-golimumab matched-pair analysis (log-rank <i>p</i> &#x3c; 0.001) and 29.5 and 25.2% in the vedolizumab-infliximab matched-pair analysis (log-rank <i>p</i> value = 0.008). Vedolizumab was associated with a significant 0.85-, 0.72-, and 0.86-fold decrease in the risk of discontinuation within 3 years of therapy initiation compared to adalimumab, golimumab, and infliximab, respectively. <b><i>Conclusions:</i></b> Treatment persistence was higher for vedolizumab than for TNF-α inhibitors up to 3 years after initiating second-line biological therapy.

scholarly journals TNF Inhibitor-Induced Psoriasis: Proposed Algorithm for Treatment and Management

2018 ◽  
Vol 4 (2) ◽  
pp. 70-80 ◽  
Author(s):  
Sara Jiayang Li ◽  
Lourdes M. Perez-Chada ◽  
Joseph F. Merola
Keyword(s):  
Tumor Necrosis ◽  
Treatment Algorithm ◽  
Psoriatic Skin ◽  
Tnf Inhibitor ◽  
Novel Treatment ◽  
Tnf Α ◽  
Inflammatory Bowel ◽  
Factor Α ◽  
Necrosis Factor

Tumor necrosis factor α (TNF-α)-targeted therapies have expanded the therapeutic options for patients with inflammatory bowel disease (IBD), rheumatoid arthritis (RA), psoriasis, and psoriatic arthritis (PsA) and have significantly improved patients’ quality of life. Paradoxically, anti-TNF-α agents may induce psoriatic eruptions or worsen preexisting psoriatic skin disease. Currently, there is no standard approach for the management of TNF inhibitor-induced psoriasis. Here, we conduct a literature review on TNF inhibitor-induced psoriasis and introduce a novel treatment algorithm for maintaining otherwise effective anti-TNF therapy versus switching to a different class as appropriate in the management of patients with IBD, RA, psoriasis, or PsA.

scholarly journals Fcγ-receptor signaling augments the LPS-stimulated increase in serum tumor necrosis factor-α levels

2001 ◽  
Vol 280 (4) ◽  
pp. R1037-R1044 ◽  
Author(s):  
Marion L. Refici ◽  
Dennis W. Metzger ◽  
Bernard P. Arulanandam ◽  
Michelle R. Lennartz ◽  
Daniel J. Loegering
Keyword(s):  
Tumor Necrosis Factor ◽  
Complement Activation ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Fcγ Receptor ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor ◽  
Serum Tumor Necrosis

The phagocytosis of IgG-coated erythrocytes (EIgG) has been shown to augment the bacterial lipopolysaccharide (LPS)-stimulated increase in serum tumor necrosis factor-α (TNF-α) levels. The present study evaluated the role of Fcγ-receptor (FcγR) signaling and complement activation in the effect of EIgG on the TNF-α response to LPS. The role of FcγR was determined using FcR γ-chain knockout mice that lack functional FcγRI and FcγRIII. In wild-type animals, EIgG caused a 16-fold augmentation of the serum TNF-α response to LPS, whereas there was no augmentation in the FcγR-deficient animals. Heat-damaged erythrocytes also augmented the TNF-α response to LPS. This effect was absent in FcγR-deficient animals. An IgG antibody against heated erythrocytes was detected in mouse serum. The complement activation caused by EIgG had little effect on the LPS-stimulated increase in serum TNF-α levels as indicated by activation of complement with cobra venom factor or IgM-coated erythrocytes as well as studies with C5-deficient mice. These results indicate that FcγR signaling primarily mediates the augmented serum TNF-α response to LPS caused by EIgG.

scholarly journals CD14 Counterregulates Lipopolysacharide-Induced Tumor Necrosis Factor-α Production in a Macrophage Subset

2019 ◽  
Vol 11 (4) ◽  
pp. 359-374 ◽  
Author(s):  
Anja Grahnert ◽  
Ronald Weiss ◽  
Erik Schilling ◽  
Nancy Stanslowsky ◽  
Ulrich Sack ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Decisive Role ◽  
Interleukin 10 ◽  
Primary Response ◽  
Mitogen Activated Protein Kinase ◽  
Experimental Conditions ◽  
Expression Levels ◽  
Tnf Α ◽  
Necrosis Factor

In response to GM-CSF or M-CSF, macrophages (MΦ) can acquire pro- or anti-inflammatory properties, respectively. Given the importance of CD14 and Toll-like receptor (TLR) 4 in lipopolysaccharide (LPS)-induced signaling, we studied the effect of anti-CD14 antibody mediated CD14 blockade on LPS-induced cytokine production, signal transduction and on the expression levels of CD14 and TLR4 in GM-MΦ and M-MΦ. We found M-MΦ to express higher levels of both surface antigens and to produce more interferon (IFN)-β and interleukin-10, but less tumor necrosis factor (TNF)-α than GM-MΦ. Blockage of CD14 at high LPS concentrations increased the production of proinflammatory cytokines and decreased that of IFN-β in M-MΦ but not in GM-MΦ. We show that phosphorylation states of signaling molecules of the MyD88 (myeloid differentiation primary response 88), TRIF (TIR-domain-containing adapter-inducing IFN-β) and MAPK (mitogen-activated protein kinase) pathways are not altered in any way that would account for the cytokine overshoot reaction. However, CD14 blockage in M-MΦ decreased TLR4 and CD14 expression levels, regardless of the presence of LPS, indicating that the loss of the surface molecules prevented LPS from initiating TRIF signaling. As TNF-α synthesis was even upregulated under these experimental conditions, we suggest that TRIF is normally involved in restricting LPS-induced TNF-α overproduction. Thus, surface CD14 plays a decisive role in the biological response by determining LPS-induced signaling.

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