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-126232
    Verproside
    		Inhibitor
    Verproside, a catalpol derivative iridoid glycoside isolated from the genus Pseudolysimachion, represses TNF-α -induced MUC5AC expression by inhibiting NF-κB activation via the IKK/IκB signaling cascade. Verproside has potent anti-inflammatory, antioxidant, antinociceptive and anti-asthmatic activities. Verproside has the potential for the study of chronic obstructive pulmonary disease (COPD).
    Verproside
  • HY-W338346
    Salicylate choline
    		Inhibitor
    Salicylate choline is an orally active derivative of Aspirin (acetylsalicylic acid) (HY-14654). Salicylate choline significantly reduces IL-1β, IL-6, TNF-α and IL-10 levels in cells. Salicylate choline enhances the anti-tumor activity of the CRM1 inhibitor Selinexor (KPT-330) (HY-17536) through inducing S-phase cell cycle arrest and impairing DNA damage repair. Salicylate choline combined with Selinexor demonstrates excellent anti-tumor efficacy in mice xenograft model harboring JeKo-1 cells. Salicylate choline can be used for the study of rheumatic diseases, inflammation and cancer.
    Salicylate choline
  • HY-N19727
    Chamissonolide
    		Inhibitor
    Chamissonolide is a sesquiterpene lactone with cytotoxic, anti-inflammatory and trypanocidal activities. Chamissonolide reduces the mRNA levels of IL-2, IFN-γ, GM-CSF, iNOS and TNF-α, and upregulates the mRNA level of NF-ATc. Chamissonolide decreases the population of naturally occurring apoptotic cells. Chamissonolide can be used in research related to tumors, African trypanosomiasis and Chagas disease.
    Chamissonolide
  • HY-147141A
    HS-276 hydrochloride
    		Inhibitor
    HS-276 hydrochloride is an orally active, potent and highly selective TAK1 inhibitor, with a Ki of 2.5 nM. HS-276 hydrochloride shows significant inhibition of TAK1, CLK2, GCK, ULK2, MAP4K5, IRAK1, NUAK, CSNK1G2, CAMKKβ-1, and MLK1, with IC50 values of 8.25, 29, 33, 63, 125, 264, 270, 810, 1280, and 5585 nM, respectively. HS-276 hydrochloride reduces the expression of TNF, IL-6, and IL-1β. HS-276 hydrochloride can be used for rheumatoid arthritis (RA) research.
    HS-276 hydrochloride
  • HY-N3421
    Koaburaside
    		Inhibitor
    Koaburaside is a cytoprotective and anti-inflammatory natural compound. Koaburaside shows antioxidant activity with an IC50 of 9.0 μM for DPPH-free radical scavenging assay. Koaburaside inhibits histamine release and expressions of IL-6 and TNF-α in human mast cells. Koaburaside also effectively inhibits influenza A neuraminidase.
    Koaburaside
  • HY-175250
    TNF-α-IN-25
    		Inhibitor
    TNF-α-IN-25 is an orally active TNF-α inhibitor. TNF-α-IN-25 shows Fluorescence Polarization (FP) assay IC50 of 103 nM in FP binding assays and L929 assay IC50 of 505 nM in cell-based assays. TNF-α-IN-25 inhibits paw swelling in the glucose-6-phosphate isomerase (GPI) arthritis model. TNF-α-IN-25 can be used for the study of arthritis.
    TNF-α-IN-25
  • HY-171837A
    t9,t11,c15-CLNA
    		Inhibitor
    t9,t11,c15-CLNA is a conjugated linolenic acid (CLNA) isomer produced by Lactobacillus plantarum ZS2058. t9,t11,c15-CLNA has the main activities of anti-inflammatory, antioxidant and improving intestinal barrier function. The regulatory mechanism of t9,t11,c15-CLNA includes upregulation of tight junction proteins, inhibition of pro-inflammatory cytokines (such as TNF-α, IL-6) and activation of antioxidant enzymes (such as SOD, CAT). t9,t11,c15-CLNA can be used in the study of inflammatory bowel diseases (such as colitis).
    t9,t11,c15-CLNA
  • HY-181646
    PDE4-IN-34
    		Inhibitor
    PDE4-IN-34 is a phosphodiesterase 4 (PDE4) inhibitor, with IC50 values of 19 pM and 14 pM against PDE4B1 and PDE4D2, respectively. PDE4-IN-34 shows weak inhibitory activity against PDE8A1, with an IC50 value of 4.092 μM, and exhibits significant selectivity over other subtypes (IC50 > 10 μM). PDE4-IN-34 improves pulmonary function, reduces inflammatory responses and alleviates lung tissue damage in a rat model induced by cigarette smoke combined with LPS (HY-D1056). PDE4-IN-34 can be used for research related to chronic obstructive pulmonary disease.
    PDE4-IN-34
  • HY-153504
    TACE-IN-1
    		Inhibitor
    TACE-IN-1 is an orally active hydantoin-based tumor necrosis factor-α converting enzyme (TACE) inhibitor. TACE-IN-1 inhibits the production of TNF-α in human whole blood. TACE-IN-1 can be prepared as a stable neutral form. TACE-IN-1 can be used in anti-inflammatory research.
    TACE-IN-1
  • HY-P990304B
    Anti-Mouse 4-1BBL/CD137L (D265A) Antibody (TKS-1)
    		Inhibitor
    Anti-Mouse 4-1BBL/CD137L (D265A) Antibody (TKS-1) is a mouse-derived IgG1 κ antibody inhibitor that targets mouse 4-1BBL/CD137L. Anti-Mouse 4-1BBL/CD137L (D265A) Antibody (TKS-1) is a chimeric version of the original TKS-1 antibody (HY-P990304). The variable domain sequences are identical to the original TKS-1 but the constant region sequences have been switched from rat IgG2a to mouse IgG1. Anti-Mouse 4-1BBL/CD137L (D265A) Antibody (TKS-1) contains a D265A mutation in the Fc fragment rendering it unable to bind to endogenous Fcγ receptors. Anti-Mouse 4-1BBL/CD137L (D265A) Antibody (TKS-1) reacts with mouse 4-1BB ligand (4-1BBL). Anti-Mouse 4-1BBL/CD137L (D265A) Antibody (TKS-1) can be used for the researches of cancer, infection, inflammation and immunology.
    Anti-Mouse 4-1BBL/CD137L (D265A) Antibody (TKS-1)
  • HY-N12104
    Trichodimerol
    		Inhibitor
    Trichodimerol (BMS-182123) is a TNF-α promoter inhibitor that inhibits the activity of lipopolysaccharide-induced cytokine secretion. Trichodimerol inhibits lipopolysaccharide-induced TNF-α promoter activity, reduces steady-state TNF-α mRNA expression, and does not alter the stability of TNF-α mRNA. Trichodimerol inhibits lipopolysaccharide-induced TNF-α secretion in murine and human immune cells. Trichodimerol reduces lipopolysaccharide-induced IL-1β secretion by 25%-50% in vitro. Trichodimerol does not alter total protein synthesis or constitutive lysozyme secretion at effective concentrations. Trichodimerol can be used for the research of septic shock.
    Trichodimerol
  • HY-162850
    DOR agonist 2
    		Inhibitor
    DOR agonist 2 (Compound 3) is a Delta Opioid Receptor agonist. DOR agonist 2 can inhibit the expression of TNF-α, prevent NF-κB transport to the nucleus, and activate the G protein-mediated ERK1/2 pathway. DOR agonist 2 can be used in the study of neurodegenerative diseases.
    DOR agonist 2
  • HY-183764
    COX-2/5-LOX-IN-8
    		Inhibitor
    COX-2/5-LOX-IN-8 is an orally active dual COX-2/5-LOX inhibitor, with an IC50 of 6.30 μM against sheep-derived COX-2 and an IC50 of 8.09 μM against 5-LOX. COX-2/5-LOX-IN-8 acts as a membrane stabilizer that stabilizes erythrocyte membranes against hypotonicity-induced hemolysis. COX-2/5-LOX-IN-8 functions as a protein stabilizer that inhibits heat-induced denaturation of bovine serum albumin. COX-2/5-LOX-IN-8 reduces paw swelling, improves hind limb weight-bearing function, decreases serum levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, CRP), and lowers serum levels of cartilage degradation biomarkers (COMP, MMP-3, CTX-II). COX-2/5-LOX-IN-8 can be used in the research of osteoarthritis.
    COX-2/5-LOX-IN-8
  • HY-117569
    KF24345 free base
    		Inhibitor
    KF24345 free base is an orally active adenosine uptake inhibitor. KF24345 free base inhibits adenosine uptake by human, mouse, rabbit and hamster erythrocytes with IC50 values of 59.5, 130.1, 104.2 and 30.9 nM, respectively. KF24345 free base has anti-inflammatory activity and can inhibit LPS-induced TNF-α production and leukopenia in mice.
    KF24345 free base
  • HY-N0633R
    Muscone (Standard)
    		Inhibitor
    Muscone (Standard) is the analytical standard of Muscone. This product is intended for research and analytical applications. Muscone is the main active monomer of traditional Chinese medicine musk. Muscone inhibits NF-κB and NLRP3 inflammasome activation. Muscone remarkably decreases the levels of inflammatory cytokines (IL-1β, TNF-α and IL-6), and ultimately improves cardiac function and survival rate.
    Muscone (Standard)
  • HY-174405
    PROTAC PDE4 degrader-1
    		Inhibitor
    PROTAC PDE4 degrader-1 (Compound 9m) is a selective and orally active PDE4 PROTAC degrader with a DC50 of 41.98 μM. PROTAC PDE4 degrader-1 potently inhibits the secretion of pro-inflammatory cytokines such as TNF-α and IL-6. PROTAC PDE4 degrader-1 significantly alleviates pulmonary inflammation in LPS (HY-D1056)-induced acute lung injury (ALI) mice Model. Pink: PDE4 ligand (HY-174410); Blue: CRBN ligase ligand (HY-10984); Black: linker
    PROTAC PDE4 degrader-1
  • HY-N16066
    Candidusin A
    		Inhibitor
    Candidusin A (CHNQD-0803) (Compound 4) is a AMPK activator with a KD of 47.28 nM. Candidusin A can be isolated from marine fungus Aspergillus candidus. Candidusin A has cytotoxic activity and induces apoptosis in human prostate cancer cells (22Rv1, PC-3 and LNCaP cells). Candidusin A reduces adipogenesis genes expression and fat deposition, negatively regulates the NF-κB-TNFα inflammatory axis to suppress inflammation, and ameliorates liver injury and fibrosis. Candidusin A can be used for non-alcoholic steatohepatitis (NASH) research.
    Candidusin A
  • HY-178287
    TNF-α-IN-27
    		Inhibitor
    TNF-α-IN-27 (Compound 1) is a TNF-α inhibitor with inhibition rate of 64% at 10 μM. TNF-α-IN-27 can be used for the researches of inflammation and immunology, such as asthma.
    TNF-α-IN-27
  • HY-178983
    SHP2-IN-45
    		Inhibitor
    SHP2-IN-45 (Compound 6) is a potent, highly selective, and orally active SHP2 allosteric inhibitor. SHP2-IN-45 significantly reduces the expressions of IL-6, TNF-α, IL-1β, and iNOS. SHP2-IN-45 inhibits the polarization of M1-type macrophages. SHP2-IN-45 can inhibit the NF-κB pathway. SHP2-IN-45 can be used in the research of sepsis and acute lung injury.
    SHP2-IN-45
  • HY-P991778
    Anti-Mouse BAFF-R Antibody (9B9)
    		Inhibitor
    Anti-Mouse BAFF-R Antibody (9B9) reacts with mouse B-cell activating factor receptor (BAFF-R). Anti-Mouse BAFF-R Antibody (9B9) blocks BAFF-R both in vivo and in vitro. Recommend Isotype Controls: Rat IgG2b kappa, Isotype Control (HY-P990682).
    Anti-Mouse BAFF-R Antibody (9B9)
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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