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-N4100
    Trilobatin
    		98.97%
    Trilobatin, a natural sweetener derived from Lithocarpus polystachyus Rehd, Trilobatin is an HIV-1 entry inhibitor targeting the HIV-1 Gp41 envelope. Neuroprotective effects. Trilobatin is also a SGLT1/2 inhibitor that selectively induces the proliferation of human hepatoblastoma cells.
    Trilobatin
  • HY-P1068
    Lysozyme
    		Inhibitor
    Lysozyme (Muramidase) is a conserved antimicrobial protein. Lysozyme exerts its bactericidal effect by hydrolyzing bacterial cell wall peptidoglycan (PG). Lysozyme plays an important role in limiting bacterial growth on mucosal surfaces and other sites, not only controlling potential pathogens but also limiting overgrowth of microbiota to prevent dysbiosis. Extracellular lysozyme can also degrade polymeric PG into soluble fragments, activate NOD receptors in mucosal epithelial cells, and lead to the secretion of chemokines and activating factors by neutrophils and macrophages.
    Lysozyme
  • HY-150725
    ODN 1585
    		Inducer
    ODN 1585 is a potent inducer of IFN and TNFα production. ODN 1585 is a potent stimulator of NK (natural killer) function. ODN 1585 increases CD8+ T-cell function, including the CD8+ T cell-mediated production of IFN-γ. ODN 1585 induces regression of established melanomas in mice. ODN 1585 can confer complete protection against malaria in mice. ODN 1585 can be used for acute myelogenous leukemia (AML) and malaria research. ODN 1585 can be used as a vaccine adjuvant.
    ODN 1585
  • 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-150725C
    ODN 1585 sodium
    		Inducer
    ODN 1585 sodium is a potent inducer of IFN and TNFα production. ODN 1585 sodium is a potent stimulator of NK (natural killer) function. ODN 1585 sodium increases CD8+ T-cell function, including the CD8+ T cell-mediated production of IFN-γ. ODN 1585 sodium induces regression of established melanomas in mice. ODN 1585 sodium can confer complete protection against malaria in mice. ODN 1585 sodium can be used for acute myelogenous leukemia (AML) and malaria research. ODN 1585 sodium can be used as a vaccine adjuvant.
    ODN 1585 sodium
  • HY-15509A
    Semapimod tetrahydrochloride
    		Inhibitor 98.43%
    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-P99670
    Iscalimab
    		Inhibitor 99.64%
    Iscalimab (CFZ-533) is a non-depleting IGg1 monoclonal antibody targeting CD40 (KD: 0.3 nM). Iscalimab can be used for research of Graves' hyperthyroidism and autoimmune diseases.
    Iscalimab
  • HY-P9989
    Linvoseltamab
    		Inhibitor 99.71%
    Linvoseltamab (REGN5458) is a bispecific T-cell engager (BiTE) antibody that specifically binds to B cell maturation antigen (BCMA) and CD3 of T cells, thereby directing T cells to multiple myeloma (MM) cells expressing BCMA and activating T cells to kill tumor cells. Linvoseltamab can be used in research of relapsed/refractory multiple myeloma (RRMM).
    Linvoseltamab
  • HY-P99742
    Mitazalimab
    		Inhibitor 99.23%
    Mitazalimab (ADC-1013; JNJ-64457107) is FcγR-dependent CD40 agonist with tumor-directed activity. Mitazalimab activates antigen-presenting cells, e.g. dendritic cells (DC), to initiate tumor-reactive T cells. Therefore, Mitazalimab induces tumor-specific T cells to infiltrate and kill tumors. Mitazalimab remodels the tumor-infiltrating myeloid microenvironment.
    Mitazalimab
  • HY-103435
    Vialinin A
    		Inhibitor 99.90%
    Vialinin A (Terrestrin A) is a p-terphenyl compound that can be derived from a Chinese edible mushroom. Vialinin A is an inhibitor of ubiquitin-specific peptidase 4 (USP4) and has anti-inflammatory and antioxidant properties. Vialinin A can alleviate cerebral ischaemia-reperfusion injury-induced neurological deficits and neuronal apoptosis. Vialinin A promotes activation of Keap1-Nrf2-ARE signaling pathway and increases the protein degradation of Keap1. Vialinin A possesses various pharmacological activities in cancer, Kawasaki disease, asthma, and pathological scarring. Vialinin A is a potent inhibitor of TNF-α, USP4, USP5, and sentrin/SUMO-specific protease 1 (SENP1). Vialinin A can be studied in reseach for autoimmune diseases, cancer and ischaemic stroke.
    Vialinin A
  • HY-111255A
    SPD304 dihydrochloride
    		Inhibitor 99.82%
    SPD304 dihydrochloride is a selective TNF-α inhibitor, which promotes dissociation of TNF trimers and therefore blocks the interaction of TNF and its receptor. SPD304 has an IC50 of 22 μM for inhibiting in vitro TNF receptor 1 (TNFR1) binding to TNF-α.
    SPD304 dihydrochloride
  • HY-Y0148
    10-Hydroxydecanoic acid
    		Inhibitor 99.77%
    10-Hydroxydecanoic acid (10-HDAA) is a saturated fatty acid derived from 10-hydroxy-trans-2-decenoic acid, which can be isolated from royal jelly. 10-Hydroxydecanoic acid exhibits various biological activities, including anti-inflammatory, insecticidal, anti-malarial, and anti-Leishmania properties, as well as enhancing antigen-specific immune responses. The anti-inflammatory effects of 10-Hydroxydecanoic acid are primarily mediated by inhibiting the activation of NF-κB and the translation of interferon regulatory factor 1 (IRF-1), which reduces the production of interleukin 6 (IL-6) and nitric oxide (NO) in inflammatory cells. Additionally, 10-Hydroxydecanoic acid alleviates neuroinflammatory responses through the p53-autophagy pathway and the p53-NLRP3 pathway. Finally, 10-Hydroxydecanoic acid enhances antigen-specific immune responses by promoting the effective uptake of antigens by microfold cells.
    10-Hydroxydecanoic acid
  • HY-100755
    KR-33493
    		Inhibitor 99.94%
    KR-33493 is a potent inhibitor of Fas-mediated cell death (FAF1).
    KR-33493
  • HY-P99315
    Ruplizumab
    		Inhibitor 99.84%
    Ruplizumab (BG 9588) is a humanized anti-CD40L IgG1κ monoclonal antibody. By binding to CD40L, Ruplizumab blocks its interaction with the CD40 receptor, inhibits T-B cell costimulatory signals, and mediates the depletion of activated T cells via the Fc segment. Ruplizumab has immunosuppressive effects. Ruplizumab can be used in the study of systemic lupus erythematosus, organ transplant rejection, and autoimmune diseases. Recommend Isotype Controls: Human IgG1 kappa, Isotype Control (HY-P99001).
    Ruplizumab
  • HY-P99148
    Anti-Mouse/Rat/Rabbit TNF alpha Antibody (TN3-19.12)
    		Inhibitor
    Anti-Mouse TNF alpha Antibody (TN3-19.12) is an anti-mouse TNF alpha IgG antibody inhibitor derived from host Armenian Hamster. Anti-Mouse TNF alpha Antibody (TN3-19.12) neutralizes cytotoxic activity in supernatants obtained from LNC-8 cells. Anti-Mouse TNF alpha Antibody (TN3-19.12) reduces the symptoms and severity of EAE (experimental allergic encephalomyelitis) in LNC-8 cells xenograft mice models. Anti-Mouse TNF alpha Antibody (TN3-19.12) prevents diabetes in NOD mice. Anti-Mouse TNF alpha Antibody (TN3-19.12) shows apparent radiosensitizing effect in CD2F1 mice.
    Anti-Mouse/Rat/Rabbit TNF alpha Antibody (TN3-19.12)
  • HY-N0182R
    Fisetin (Standard)
    		Inhibitor
    Fisetin (Standard) is the analytical standard of Fisetin. This product is intended for research and analytical applications. Fisetin is a natural flavonol found in many fruits and vegetables with various benefits, such as antioxidant, anticancer, neuroprotection effects.
    Fisetin (Standard)
  • HY-N0507
    Rosavin
    		Inhibitor 99.99%
    Rosavin, an orally bioactive phenylpropanoid from Rhodiola rosea L. (RRL), is an adaptogen that enhances the body’s response to environmental stress. Rosavin significantly influences bone tissue metabolism by inhibiting osteoclastogenesis and promoting osteoblast differentiation, also impacts various diseases, demonstrating antidepressant, adaptogenic, and anxiolytic effects in mouse models. Additionally, Rosavin improves survival, reducing intestinal damage in irradiated rats and Ischemia-reperfusion(I/R)-induced cerebral injury in vivo by regulating inflammation and oxidative stress, making it a promising candidate for research in radiation-induced intestinal injury, I/R-induced cerebral injury and osteoporosis.
    Rosavin
  • HY-B0367
    Lornoxicam
    		Activator 99.36%
    Lornoxicam (Chlortenoxicam) is an orally active oxycontin nonsteroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory, antipyretic and anticancer activities. Lornoxicam exhibits good inhibitory effects on both COX-1 and COX-2 (COX-1: IC50=0.005 μM; COX-2:IC50=0.008 μM) and inhibits the production of NO by iNOS (IC50=65 μM) and the proinflammatory cytokine IL-6 (IC50=54 μM). Lornoxicam also inhibits tumor cell proliferation and migration and induces tumor cell apoptosis. Lornoxicam can be used in the study of inflammatory pain, colorectal cancer and breast cancer.
    Lornoxicam
  • HY-30235A
    Benzydamine hydrochloride
    		Inhibitor 99.21%
    Benzydamine hydrochloride is an orally administered prostaglandin synthesis inhibitor that has anti-inflammatory, analgesic, antipyretic, and antibacterial properties. Benzydamine hydrochloride can inhibit TNF-α, stabilize cell membranes, and reduce oxidative stress within cells.
    Benzydamine hydrochloride
  • HY-124750
    NecroX-7
    		Inhibitor 99.69%
    NecroX-7 is a potent free radical scavenger and a HMGB1 (high-mobility group box 1) inhibitor. NecroX-7 can be used as an antidote to acetaminophen toxicity. NecroX-7 exerts a protective effect by preventing the release of HMGB1 in ischemia/reperfusion injury. NecroX-7 inhibits the HMGB1-induced release of TNF and IL-6, as well as the expression of TLR-4 and receptor for advanced glycation end products. NecroX-7 can be used graft-versus-host disease (GVHD) research.
    NecroX-7
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. 
 

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