TNFR signalling and its clinical implications

Tseng, Wen-Yi; Huang, Yi-Shu; Lin, Hsi‐Hsien; Luo, Shue‐Fen; McCann, Fiona E.; McNamee, Kay; Clanchy, Felix I. L.; Williams, Richard O.

doi:10.1016/j.cyto.2016.08.027

Cited by 41 publications

(39 citation statements)

References 119 publications

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“…TNF-α stimulates monocytes/macrophages, fibroblasts, and endothelial cells to produce IL-l and IL-6 or chemokines (CXCL8, CCL2), which are heavily involved in the pathogenesis of RA including leukocytes infiltration and tissue destruction. Inflammation induced by IL-1 and TNF-α can lead to the increased expression of the matrix metalloproteinase, collagenase, and elastase during the pathogenesis of RA, which is responsible for cartilage degradation and bone resorption (6,7). TNF-α affects the target cell via two receptors, TNF-RI (TNFRSF1A) and TNF-RII (TNFRSF1B).…”

Section: Introductionmentioning

confidence: 99%

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Association Study of Tumor Necrosis Factor Receptor Type II Polymorphism (196R) with Rheumatoid Arthritis in Iranian People

Aminikhoo

Pak

Ahmadi

et al. 2019

Middle East J Rehabil Health Stud

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Background: Rheumatoid arthritis (RA) is a common autoimmune disease characterized by inflammation. It mainly affects joints and nearby tissues. Tumor necrosis factor (TNF) is the main role-player in the pathogenesis of RA. It binds to both TNF receptors namely TNF-RI and TNF-RII. Several studies have indicated a relationship between the TNF-RII 196R/R genotype with increased production of cytokines and susceptibility to inflammatory diseases and autoimmune disorders. Objectives: Therefore, the present study aimed to investigate the association between TNF-RII polymorphism and RA. It also aimed to study the predictive value of the TNF-RII 196R allele for patients' susceptibility to RA. Methods: A total of 100 patients and 100 controls were enrolled in the study and their peripheral blood DNA was extracted. Allelic discrimination was performed between case and control groups to investigate the association between the functional TNF-RII 196R polymorphism and RA. Screening analysis for genotyping of TNF-RII functional polymorphism was performed by the TaqMan allelic discrimination assay using real-time PCR. Results: There was a significant difference between cases and controls in terms of the distribution of TNF-RII genotypes (TT, TG, GG). Correlation analysis showed an association between the G mutant allele and functional 196R polymorphism (CI = 95%, OR = 2.6, P = 0.035). Conclusions: According to our results, there is a significant correlation between TNF-RII polymorphism and the risk of RA.

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Section: Introductionmentioning

confidence: 99%

“…TNF binding to TNF-RI triggers apoptosis while its binding to TNF-RII triggers cell survival. Both TNF-RI and TNF-RII are expressed in the synovial tissue in patients with RA (7,9). The TNF-RI and TNF-RII genes are located on chromosomes 12p13 and 1p36, respectively (10).…”

Section: Introductionmentioning

confidence: 99%

Association Study of Tumor Necrosis Factor Receptor Type II Polymorphism (196R) with Rheumatoid Arthritis in Iranian People

Aminikhoo

Pak

Ahmadi

et al. 2019

Middle East J Rehabil Health Stud

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“…7,8 Importantly, the two TNF receptors exhibit diametrically opposed (dichotomic) activities, with TNFR1 being primarily responsible for proinflammatory responses and TNFR2 primarily involved in tissue homeostasis, protection and regeneration. [9][10][11][12] The approved anti-TNF agents neutralize both tmTNF and sTNF, thus globally blocking TNF activities. 13 Various adverse effects are related to this global inhibition, including common and opportunistic infections, reactivation of latent tuberculosis, lupus-like symptoms, demyelination, psoriasis, sarcoidosis, and an increase of malignancies, such as lymphomas.…”

Section: Introductionmentioning

confidence: 99%

Monovalent TNF receptor 1-selective antibody with improved affinity and neutralizing activity

Richter

Zettlitz

Seifert

et al. 2018

mAbs

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Selective inhibition of tumor necrosis factor (TNF) signaling through the proinflammatory axis of TNFreceptor 1 (TNFR1) while leaving pro-survival and regeneration-promoting signals via TNFR2 unaffected is a promising strategy to circumvent limitations of complete inhibition of TNF action by the approved anti-TNF drugs. A previously developed humanized antagonistic TNFR1-specific antibody, ATROSAB, showed potent inhibition of TNFR1-mediated cellular responses. Because the parental mouse antibody H398 possesses even stronger inhibitory potential, we scrutinized the specific binding parameters of the two molecules and revealed a faster dissociation of ATROSAB compared to H398. Applying affinity maturation and re-engineering of humanized variable domains, we generated a monovalent Fab derivative (13.7) of ATROSAB that exhibited increased binding to TNFR1 and superior inhibition of TNF-mediated TNFR1 activation, while lacking any agonistic activity even in the presence of crosslinking antibodies. In order to improve its pharmacokinetic properties, several Fab13.7-derived molecules were generated, including a PEGylated Fab, a mouse serum albumin fusion protein, a half-IgG with a dimerization-deficient Fc, and a newly designed Fv-Fc format, employing the knobs-into-holes technology. Among these derivatives, the Fv13.7-Fc displayed the best combination of improved pharmacokinetic properties and antagonistic activity, thus representing a promising candidate for further clinical development.

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“…IL-10 ve prostaglandin ise salınımını baskılar. 2 Kortikosteroidler de transkripsiyon azaltımı ile TNF üretimi üzerinde baskı kurmaktadır. Bu etkinin inhibitör kappa-β'nın ekspresyonundaki artış ve nükleer faktör kappa β (Nf-κβ)'nın aktivasyonunun engellenmesi ile sağlandığı düşünülmektedir.…”

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What is Tumor Necrosis Factor Alpha ?

Çayakar¹

2018

Turkiye Klinikleri J Intern Med

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Nedir Bu Tümör Nekrozis Faktör Alfa ? Ö ÖZ ZE ET T Tümör nekrozis faktör-alfa (TNF-α), esas olarak monosit ve makrofajlar tarafından sentezlenen 212 aminoasidin kullanımıyla oluşmuş, üç monomerli glikoprotein yapısında bir sitokindir. Otoimmün hastalıklarda inflamasyonun başlamasında ve devam ettirilmesinde önemli özellikleri bulunmaktadır. Sentez ve salınımını başlatan birçok uyaran söz konusu olup, en başlıcası lipopolisakkaritlerdir. Hem membranöz hem de solubl formu biyolojik olarak aktiftir. Etkilerini hücrelerin yüzeyindeki TNF reseptör 1'e bağlanarak göstermektedir. Reseptörünün de yapısı trimerik şekilde olup, dört sisteinden zengin yineleyen bölge içermektedir. Uyarı sonrası sinyal kaskatı üç ana yol izleyerek ileriye doğru akmaktadır. İlk ikisi nükleer faktör kappa κ (NF-κ) ve aktivatör protein-1 ile özellikle inflamasyon sürecinde, üçüncü yol ise apoptoz oluşmasında etkindir. Neticede pleiotropik etkileri söz konusudur, yani inflamatuar hastalıkların seyri sırasında değişik evrelerde çeşitli hücrelerde farklı farklı etkileri gün yüzüne çıkmaktadır. TNF-α yanıtı genetik kontrol altındadır ve anlamlı bireysel farklılıklar göstermektedir. TNF-α'yı kodlayan gen 6. kromozom üzerindeki majör histokompatibilite kompleksi içinde yer almaktadır. Gen ekspresyonu hem transkripsiyonel hem de posttranskripsiyonel şekilde regüle edilmektedir. Reseptörünün geni ise 12. kromozomun kısa kolunda bulunmaktadır. 10. eksonda gelişen mutasyonlar sonucu tümör nekrozis faktör reseptör ilişkili periyodik sendrom (TRAPS) adında otoinflamatuar bir sendrom gelişmektedir. TRAPS'ın klinik tablosunda yanlış katlanan proteinlerin endoplazmik retikulumda stres yaratması, reaktif oksĳen ürünlerinde artış yaşanması, sitokinlerin üretimlerinin artışı ve inflamatuar ataklar söz konusudur. Günümüzde TNF-α etkilerini yok etmek adına klinik kullanımda beş spesifik anti-TNF ilaç bulunmaktadır. A An na ah ht ta ar r K Ke el li im me el le er r: : Tümör nekroze edici faktör-alfa; reseptörler; tümör nekroz faktörü; tip I; peryodik ateş; ailesel; otozomal dominant A AB BS ST TR RA AC CT T Tumor necrosis factor-alpha (TNF-α) is a three monomeric glycoprotein structure composed of 212 aminoacids, which is mainly synthesized by monocytes and macrophages. It has a significant role in the initiation and progression of inflamation in the autoimmune diseases. There are a lot of stimulants that initiate its synthesis and release, particularly lipopolysaccharides. Both membraneous and soluble forms are biologically active. They exert their effects by binding to the TNF receptor 1, located in the celluler surface. The structure of the receptor is trimeric with 4 cysteine rich repeating regions. After the stimulation, signal cascade flows forward from three main routes. First two routes are active in the inflammation process by nuclear factor kappa κ (NF-κ) and activator protein-1, while 3 rd route is active in the apoptosis process. As a result, they have pleiotrophic effectswith different effectsthat arise during different stages of the inflamatory diseas...

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TNFR signalling and its clinical implications

Cited by 41 publications

References 119 publications

Association Study of Tumor Necrosis Factor Receptor Type II Polymorphism (196R) with Rheumatoid Arthritis in Iranian People

Association Study of Tumor Necrosis Factor Receptor Type II Polymorphism (196R) with Rheumatoid Arthritis in Iranian People

Monovalent TNF receptor 1-selective antibody with improved affinity and neutralizing activity

What is Tumor Necrosis Factor Alpha ?

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