2. Signaling Pathways
  3. Apoptosis
  4. TNF Receptor

TNF Receptor

Tumor Necrosis Factor Receptor; TNFR

TNF Receptor

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Tumor necrosis factor (TNF) is a major mediator of apoptosis as well as inflammation and immunity, and it has been implicated in the pathogenesis of a wide spectrum of human diseases, including sepsis, diabetes, cancer, osteoporosis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases.

TNF-α is a 17-kDa protein consisting of 157 amino acids that is a homotrimer in solution. In humans, the gene is mapped to chromosome 6. Its bioactivity is mainly regulated by soluble TNF-α–binding receptors. TNF-α is mainly produced by activated macrophages, T lymphocytes, and natural killer cells. Lower expression is known for a variety of other cells, including fibroblasts, smooth muscle cells, and tumor cells. In cells, TNF-α is synthesized as pro-TNF (26 kDa), which is membrane-bound and is released upon cleavage of its pro domain by TNF-converting enzyme (TACE).

Many of the TNF-induced cellular responses are mediated by either one of the two TNF receptors, TNF-R1 and TNF-R2, both of which belong to the TNF receptor super-family. In response to TNF treatment, the transcription factor NF-κB and MAP kinases, including ERK, p38 and JNK, are activated in most types of cells and, in some cases, apoptosis or necrosis could also be induced. However, induction of apoptosis or necrosis is mainly achieved through TNFR1, which is also known as a death receptor. Activation of the NF-κB and MAPKs plays an important role in the induction of many cytokines and immune-regulatory proteins and is pivotal for many inflammatory responses.

TNF Receptor Isoform Specific Products:

TNF Receptor Isoform Comparison
Cat. No. Product Name Effect Purity Chemical Structure
  • HY-N2963
    Broussonin E
    		Inhibitor 98.11%
    Broussonin E is a phenolic compound and shows anti-inflammatory activity. Broussonin E can suppress inflammation by modulating macrophages activation statevia inhibiting the ERK and p38 MAPK and enhancing JAK2-STAT3 signaling pathway. Broussonin E can be used for the research of inflammation-related diseases such as atherosclerosis.
    Broussonin E
  • HY-101448
    TMI-1
    		Inhibitor 99.57%
    TMI-1 (WAY-171318) inhibits TNF converting enzyme (TACE) (IC50 of 8.4 nM), ADAM-TS-4, ADAM-17 and various MMPs with oral activity. TMI-1 significantly suppresses the secretion of TNF-α , alleviating collagen-induced arthritis in mice. TMI-1 inhibits cancer cell proliferation, induces apoptosis through a caspase-dependent pathway. TMI-1 also reverses TRPV1 upregulation and lowers the levels of inflammatory factors (TNF-α、IL-1β、IL-6) in nerve cells, protecting against paclitaxel-induced neurotoxicity. TMI-1 leads to changes in pro-atherogenic lipoprotein profiles, but does not affect the progression of early lesions.
    TMI-1
  • HY-15509A
    Semapimod tetrahydrochloride
    		Inhibitor 99.18%
    Semapimod tetrahydrochloride (CNI-1493), an inhibitor of proinflammatory cytokine production, can inhibit TNF-α, IL-1β, and IL-6. Semapimod tetrahydrochloride inhibits TLR4 signaling (IC50≈0.3 μM). Semapimod tetrahydrochloride inhibits p38 MAPK and nitric oxide production in macrophages. Semapimod tetrahydrochloride has potential in a variety of inflammatory and autoimmune disorders.
    Semapimod tetrahydrochloride
  • HY-154821A
    DRI-C21041 DIEA
    		Inhibitor 99.07%
    DRI-C21041 DIEA is a CD40/CD40L interaction inhibitor, with an IC50 of 0.31 μM. DRI-C21041 DIEA inhibits the immune response induced by alloantigen.
    DRI-C21041 DIEA
  • HY-113402A
    Gamma-glutamylcysteine TFA
    		Inhibitor
    Gamma-glutamylcysteine TFA (γ-Glu-Cys TFA) is an orally active, blood-brain barrier permeable dipeptide. Gamma-glutamylcysteine TFA activates AMPK, SIRT1, IL-4/STAT6, AC/cAMP/PI3K, IGF-1R/IRS1/PI3K, and Nrf2 signaling pathways; it inhibits NF-κB, JAK1/STAT1/3, MAPKs, cadmium-induced p38 MAPK, JNK, and PI3K/Akt signaling pathways. Gamma-glutamylcysteine TFA regulates macrophage polarization, modulates the trafficking of CD36 and GLUT4, induces glutathione synthesis, improves metabolic dysfunction, reduces lipid deposition, ameliorates glucose homeostasis, inhibits apoptosis (Apoptosis), stabilizes mitochondria, suppresses lipid peroxidation, iron accumulation and ferroptosis (Ferroptosis), reduces ds-HMGB1 levels, reverses mechanical hyperalgesia, and alleviates hepatic lipid droplet formation. Gamma-glutamylcysteine TFA is applicable to research related to inflammatory bowel disease, type 2 diabetes, cadmium-induced neurotoxicity, Alzheimer's disease, cerebral ischemia/reperfusion injury, neuropathy, and alcoholic liver disease.
    Gamma-glutamylcysteine TFA
  • HY-N1887
    4-Allylcatechol
    		Inhibitor 98.60%
    4-Allylcatechol (4-Allylpyrocatechol) is a xylan which has oral activity and can be isolated from the root of Piper taiwanense. 4-Allylcatechol has a strong inhibitory activity against collagen-induced platelet aggregation (IC50 = 5.3 μM). In addition, 4-Allylcatechol has anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv (MIC = 27.6 μg/mL).
    4-Allylcatechol
  • HY-B1051
    Flumethasone
    		Inhibitor 99.84%
    Flumethasone (Flumetasone) is an orally active, high selective and potent glucocorticoid receptor (GR) agonist. Flumethasone activates GR to inhibit nuclear factor kappa B (NF-κB)-mediated pro-inflammatory cytokine production (TNF-α, IL-1β) and promotes anti-inflammatory gene expression (IL-10), while also regulating metabolic enzyme activity (tyrosine aminotransferase induction). Flumethasone is promising for research of inflammatory diseases, cancer, and endocrine regulation.
    Flumethasone
  • HY-N2350
    Cynaropicrin
    		Inhibitor 99.79%
    Cynaropicrin is a sesquiterpene lactone which can inhibit tumor necrosis factor (TNF-α) release with IC50s of 8.24 and 3.18 μM for murine and human macrophage cells, respectively. Cynaropicrin also inhibits the increase of cartilage degradation factor (MMP13) and suppresses NF-κB signaling.
    Cynaropicrin
  • HY-P990907
    Brivekimig
    		Inhibitor 98%
    Brivekimig (F-027300252; SAR-442970) is a bispecific nanobody targeting TNF/OX40L. Brivekimig is applicable to research related to hidradenitis suppurativa.
    Brivekimig
  • HY-P4846
    Ac-Pro-Gly-Pro-OH
    		Inhibitor 99.49%
    Ac-Pro-Gly-Pro-OH is an endogenous degradation product of extracellular collagen and acts as a CXCR2 agonist. Ac-Pro-Gly-Pro-OH exerts bactericidal activity by generating hydrogen peroxide, inhibits pulmonary inflammation, and reduces immune cell apoptosis (apoptosis). Ac-Pro-Gly-Pro-OH promotes the production of IFN-γ and inhibits the production of TNF-α and IL-6 in leukocytes. Ac-Pro-Gly-Pro-OH increases the survival rate of mice in sepsis models, enhances the bactericidal activity of neutrophils, acts as a neutrophil chemoattractant, induces neutrophil polarization, and regulates inflammatory and repair processes. Ac-Pro-Gly-Pro-OH induces chronic inflammation and tissue remodeling through sustained action. Ac-Pro-Gly-Pro-OH is released via alkaline hydrolysis of corneal proteins in alkali-injured eyes, thereby driving the early infiltration of neutrophils into the cornea. Ac-Pro-Gly-Pro-OH is applicable to research related to sepsis, chronic obstructive pulmonary disease, cystic fibrosis, bronchiolitis obliterans syndrome, severe asthma, idiopathic pulmonary fibrosis, and corneal ulcer.
    Ac-Pro-Gly-Pro-OH
  • HY-W082785A
    L6H21
    		Inhibitor 99.19%
    L6H21, a Chalcone (HY-121054) derivative, is an orally active, potent and specific myeloid differentiation 2 (MD-2) inhibitor. L6H21 directly binds to MD-2 protein with a high affinity and low KD value of 33.3 μM, blocking the formation of the LPS-TLR4/MD-2 complex. L6H21 inhibits LPS-induced expression of TNF-α and IL-6 in RAW264.7 macrophages, with IC50 values of 6.58 and 8.59 μM, respectively. L6H21 can be used for alcoholic liver disease, metabolic disturbance and neuroinflammation research.
    L6H21
  • HY-100735
    C 87
    		Inhibitor 98.16%
    C 87 is a novel small-molecule TNFα inhibitor; potently inhibits TNFα-induced cytotoxicity with an IC50 of 8.73 μM.
    C 87
  • HY-P99273
    Vorsetuzumab
    		Inhibitor 99.29%
    Vorsetuzumab (Anti-Human CD70 Recombinant Antibody) is a human anti-CD70 antibody. Vorsetuzumab enhances macrophage-related phagocytosis of renal carcinoma cells, shows inhibitory efficacy against Burkitt’s lymphoma.
    Vorsetuzumab
  • HY-P990134
    Anti-Mouse CD40L/CD154 Antibody (MR-1)
    		Inhibitor 99.62%
    Anti-Mouse CD40L/CD154 Antibody (MR-1) is an anti-mouse CD40L/CD154 IgG monoclonal antibody. Anti-Mouse CD40L/CD154 Antibody (MR-1) reduces the expression of IFN signaling pathway and lowers the level of IFN-β. Anti-Mouse CD40L/CD154 Antibody (MR-1) can prolong the survival time of transplants. Anti-Mouse CD40L/CD154 Antibody (MR-1) can be used for researches on cancer, inflammation conditions and xenotransplantation such as pancreatic cancer and autoimmune cholangitis.
    Anti-Mouse CD40L/CD154 Antibody (MR-1)
  • HY-N2055
    Kaempferol 3-O-sophoroside
    		Inhibitor 99.41%
    Kaempferol 3-O-sophoroside is an orally active derivative of Kaempferol. It exhibits anti-inflammatory, analgesic, and antidepressant effects. Kaempferol 3-O-sophoroside is an inhibitor of the cell surface receptor toll-like receptor (TLR) 2/4 for High mobility group box 1 (HMGB1), and it also exerts anti-inflammatory effects by blocking the activation of NF-κB expression and the production of TNF-α. Kaempferol 3-O-sophoroside promotes the production of brain-derived neurotrophic factor (BDNF) and enhances autophagy by binding to AMP-activated protein kinase (AMPK), thereby exerting antidepressant effects. Kaempferol 3-O-sophoroside holds promise for research in the fields of inflammation and neurodegenerative diseases.
    Kaempferol 3-O-sophoroside
  • HY-N1508
    Ecliptasaponin A
    		Inhibitor 99.81%
    Ecliptasaponin A is an orally active pentacyclic triterpenoid saponin. Ecliptasaponin A exerts anti-tumor activity by activating ASK1/JNK pathway, inducing apoptosis and autophagy in lung cancer cells. Ecliptasaponin A exerts anti-inflammatory/anti-fibrotic effects and protects the cardiovascular system by inhibiting the HMGB1/TLR4/NF-κB pathway, and the expression of COX-2 and MMP-9. Ecliptasaponin A can enhance SOD activity, reduce MDA levels, and alleviate oxidative stress damage. Ecliptasaponin A exerts chondroprotective effects by inhibiting the expression of MMP13 and regulating inflammatory factors. Ecliptasaponin A improves ovarian function and regulates sex hormones by upregulating the expression of ESR1 receptors.
    Ecliptasaponin A
  • HY-N0261
    Aurantio-obtusin
    		Inhibitor 99.39%
    Aurantio-obtusin is a anthraquinone compound that can be extracted from cassia seed. Aurantio-obtusin has the effects of decreasing blood pressure, decreasing blood lipids and anti-inflammatory.Aurantio-obtusin is an orally active vasodilator. Aurantio-obtusin ameliorates hepatic steatosis through AMPK/ autophagy- and AMPK/TFEB mediated inhibition of lipid accumulation.
    Aurantio-obtusin
  • HY-P991192
    BI-1808
    		Inhibitor
    BI-1808 is a human IgG1 monoclonal antibody that targets TNFR2by blocking interaction of TNFR2 with ligand TNF-α, confers FcγR-dependent depletion of Treg and mediates expansion of intratumoral CD8+ T cells.
    BI-1808
  • HY-124339
    JNJ525
    		Inhibitor 99.93%
    JNJ525 is a TNFα inhibitor with IC50 values of 1.2 μM and 1.1 μM against TNFR1 and TNFR2, respectively. JNJ525 forms ordered aggregates and induces quaternary structural transition of TNFα, thereby blocking the protein-protein interaction between TNFα and its receptors. The inhibitory activity of JNJ525 is completely lost in the presence of 0.1% Triton X-100.
    JNJ525
  • HY-N0723
    Neomangiferin
    		Inhibitor 99.80%
    Neomangiferin is an orally active natural flavonoid. Neomangiferin partially ameliorates non-alcoholic fatty liver disease (NAFLD) by regulating the expression of genes related to free fatty acid uptake and lipid oxidation. Neomangiferin exerts anti-colitis effects by inhibiting Th17/Treg cell differentiation. Neomangiferin exerts anti-aging and lifespan-extending effects by targeting upregulation of bas-1, which in turn activates the autophagy, IIS and MAPK pathways. Neomangiferin has the potential to prevent aseptic loosening of prostheses after total joint arthroplasty due to its significant anti-inflammatory and osteoclastogenesis-inhibiting effects.
    Neomangiferin
Cat. No. Product Name / Synonyms Species Source
Cat. No. Product Name / Synonyms Application Reactivity
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Download TNF Receptor Signaling Pathway Map.

Following the binding of TNF to TNF receptors, TNFR1 binds to TRADD, which recruits RIPK1, TRAF2/5 and cIAP1/2 to form TNFR1 signaling complex I; TNFR2 binds to TRAF1/2 directly to recruit cIAP1/2. Both cIAP1 and cIAP2 are E3 ubiquitin ligases that add K63 linked polyubiquitin chains to RIPK1 and other components of the signaling complex. The ubiquitin ligase activity of the cIAPs is needed to recruit the LUBAC, which adds M1 linked linear polyubiquitin chains to RIPK1. K63 polyubiquitylated RIPK1 recruits TAB2, TAB3 and TAK1, which activate signaling mediated by JNK and p38, as well as the IκB kinase complex. The IKK complex then activates NF-κB signaling, which leads to the transcription of anti-apoptotic factors-such as FLIP and Bcl-XL-that promote cell survival. 

 

The formation of TNFR1 complex IIa and complex IIb depends on non-ubiquitylated RIPK1. For the formation of complex IIa, ubiquitylated RIPK1 in complex I is deubiquitylated by CYLD. This deubiquitylated RIPK1 dissociates from the membrane-bound complex and moves into the cytosol, where it interacts with TRADD, FADD, Pro-caspase 8 and FLIPL to form complex IIa. By contrast, complex IIb is formed when the RIPK1 in complex I is not ubiquitylated owing to conditions that have resulted in the depletion of cIAPs, which normally ubiquitylate RIPK1. This non-ubiquitylated RIPK1 dissociates from complex I, moves into the cytosol, and assembles with FADD, Pro-caspase 8, FLIPL and RIPK3 (but not TRADD) to form complex IIb. For either complex IIa or complex IIb to prevent necroptosis, both RIPK1 and RIPK3 must be inactivated by the cleavage activity of the Pro-caspase 8-FLIPL heterodimer or fully activated caspase 8. The Pro-caspase 8 homodimer generates active Caspase 8, which is released from complex IIa and complex IIb. This active Caspase 8 then carries out cleavage reactions to activate downstream executioner caspases and thus induce classical apoptosis. 

 

Formation of the complex IIc (necrosome) is initiated either by RIPK1 deubiquitylation mediated by CYLD or by RIPK1 non-ubiquitylation due to depletion of cIAPs, similar to complex IIa and complex IIb formation. RIPK1 recruits numerous RIPK3 molecules. They come together to form amyloid microfilaments called necrosomes. Activated RIPK3 phosphorylates and recruits MLKL, eventually leading to the formation of a supramolecular protein complex at the plasma membrane and necroptosis [1][2].

 

Reference:
[1]. Brenner D, et al. Regulation of tumour necrosis factor signalling: live or let die.Nat Rev Immunol. 2015 Jun;15(6):362-74. 
[2]. Conrad M, et al. Regulated necrosis: disease relevance and therapeutic opportunities.Nat Rev Drug Discov. 2016 May;15(5):348-66. 
 

TNF Receptor Isoform Comparison

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