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-N15570
    2-O-Methylatromentin
    		Inhibitor
    2-O-Methylatromentin is an anti-neuroinflammatory agent. 2-O-Methylatromentin shows inhibitory activity on the production of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β in Lipopolysaccharides (HY-D1056) (LPS) -induced BV-2 microglial cells. 2-O-Methylatromentin can be used for the study of neuroinflammatory related diseases.
    2-O-Methylatromentin
  • HY-N0297R
    Sinensetin (Standard)
    		Inhibitor
    Sinensetin (Standard) is the analytical standard of Sinensetin. This product is intended for research and analytical applications.
    Sinensetin (Standard)
  • HY-P991433
    BIIB036
    		Activator
    BIIB036 is a human IgG1 monoclonal antibody (mAb) targeting TNFRSF12A/Fn14. BIIB036 inhibits the growth of patient-derived primary colorectal tumors in SCID mice.
    BIIB036
  • HY-147247
    Fosimdesonide
    		Inhibitor
    Fosimdesonide, a small molecule of adalimumab fosimdesonide, is a potent immunomodulator. Fosimdesonide shows anti-inflammatory activity.
    Fosimdesonide
  • HY-162599
    Spirohypertone B
    		Inhibitor
    Spirohypertone B is a potent Tumor necrosis factor-α (TNF-α) inhibitor. Spirohypertone B protects L929 cells from death induced by co-incubation with TNF-α and Actinomycin D (HY-17559).
    Spirohypertone B
  • HY-P3639
    SYLQDSVPDSFQD
    SYLQDSVPDSFQD, anchor-modified for high-affinity binding to DR4, is a DR4-restricted MHC class II peptide Tyrosinase.
    SYLQDSVPDSFQD
  • HY-170586
    JAK05
    		Modulator
    JAK05 exhibits inhibitory activity against Helicobacter pylori, inhibits strains J63, J196 and J107 with MIC of 3-5 µg/mL. JAK05 exhibits binding affinity to H+/K+-ATPase, COX-1/2, TNF-α and PGE2, reveals antioxidant and anti-inflammatory activities. JAK05 exhibits anti-ulcer activity in rat ethanol-induced gastric ulcer models.
    JAK05
  • HY-149087
    MR2938
    		Inhibitor
    MR2938 is a potent AChE inhibitor, with an IC50 of 5.04 μM. MR2938 also suppresses NO production obviously (IC50 = 3.29 μM). MR2938 suppresses the neuroinflammation through blocking MAPK/JNK and NF-κB signaling pathways. MR2938 can be used for Alzheimer’s disease (AD) research.
    MR2938
  • HY-P990564
    Senlizumab
    		Inhibitor
    Senlizumab is a humanized antibody expressed in CHO cells that targets TNFSF2/TNFa. Senlizumab is composed of huIgG4SP heavy chains and huκ light chains, with a predicted molecular weight (MW) of 146.9 kDa. The isotype control for Senlizumab can refer to Human IgG4 kappa, Isotype Control (HY-P99003).
    Senlizumab
  • HY-15643B
    LY 303511 dihydrochloride
    		Activator
    LY 303511 dihydrochloride is a structural analogue of LY294002. LY 303511 dihydrochloride does not inhibit PI3K. LY 303511 dihydrochloride enhances TRAIL sensitivity of SHEP-1 neuroblastoma cells. LY 303511 dihydrochloride reversibly blocks K+ currents (IC50=64.6±9.1 μM) in MIN6 insulinoma cells.
    LY 303511 dihydrochloride
  • HY-146560
    Xanthine oxidase-IN-6
    		Inhibitor
    Xanthine oxidase-IN-6 (Compound 6c) is a potent, orally active, mixed-type xanthine oxidase (XOD) inhibitor with an IC50 value of 1.37 µM. Xanthine oxidase-IN-6 shows strong anti-hyperuricemia and renal protective activity.
    Xanthine oxidase-IN-6
  • HY-N0171AR
    Beta-Sitosterol (purity>98%) (Standard)
    		Inhibitor
    Beta-Sitosterol (purity>98%) (Standard) is an analytical standard for Beta-Sitosterol (purity>98%). Beta-Sitosterol (purity>98%) is intended for research and analytical applications. Beta-Sitosterol (purity>98%) is orally active. Beta-Sitosterol exhibits multiple activities, including anti-inflammatory, anticancer, antioxidant, antimicrobial, antidiabetic, antioxidant enzyme, and analgesic. Beta-Sitosterol inhibits inflammation and impaired adipogenesis in bovine mammary epithelial cells by reducing levels of ROS, TNF-α, IL-1β, and NF-κB p65 and restoring the activity of the HIF-1α/mTOR signaling pathway. Beta-Sitosterol induces apoptosis in cancer cells through ROS-mediated mitochondrial dysregulation and p53 activation. Beta-Sitosterol exerts its anticancer effects in cancer cells by activating caspase-3, caspase-8, and caspase-9, mediating PARP inactivation, MMP loss, altered Bcl-2-Bax ratio, and cytochrome c release. Beta-Sitosterol modulates macrophage polarization and reduces rheumatoid inflammation in mice. Beta-Sitosterol inhibits tumor growth in multiple mouse cancer models. Beta-Sitosterol can be used in the research of arthritis, lung cancer, breast cancer and other cancers, diabetes, etc.
    Beta-Sitosterol (purity>98%) (Standard)
  • HY-170723
    JAK-IN-39
    		Inhibitor
    JAK-IN-39 (compound 11) is a JAK inhibitor that suppresses JAK1, JAK2, JAK3 with IC50 values of 0.05, 1.18, and 0.03 nM, respectively. JAK-IN-39 can inhibit the viability of TF-1 cells and also suppress the production of lymphocyte TNFα and INFγ in vitro.
    JAK-IN-39
  • HY-P991557
    ABI793
    		Inhibitor
    ABI793 is a human IgG1 anti-human CD154 (CD40 ligand) monoclonal antibody. ABI793 inhibits immune response by blocking the CD154-CD40 (IC50 = 75 nM) signaling pathway. ABI793 effectively prevents kidney transplant rejection. ABI793 can be used for research on immunological rejection.
    ABI793
  • HY-175082
    TBPH
    		Agonist
    TBPH is a brominated flame retardant. TBPH enhances hepatic steatosis, inflammation, and fibrosis in mice with nonalcoholic steatohepatitis (NASH). TBPH induces dysregulation of phospholipid metabolism, reducing cardiolipin (CL) and phosphatidylserine (PS) levels. TBPH leads to impaired endoplasmic reticulum-mitochondria (ER-Mito) contacts, subsequently causing mitochondrial dysfunction. TBPH induces lung injury through an inflammatory response mediated by mitochondria-derived ds-DNA. TBPH can be used to study the role of MFN2-mediated ER-mitochondria contacts in lipid metabolism homeostasis.
    TBPH
  • HY-168971
    Paeoniflorin-6′-O-benzene sulfonate
    		Antagonist
    Paeoniflorin-6′-O-benzene sulfonate (CP-25) is the inhibitor for G protein-coupled receptor kinase 2 (GRK2) that inhibits the translocation of GRK2 to the cell membrane, inhibits JAK1/STAT3 signaling pathway. Paeoniflorin-6′-O-benzene sulfonate inhibits IL-17A/CXCL2-induced proliferation of HaCaT. Paeoniflorin-6′-O-benzene sulfonate reduces the levels of inflammatory factors and chemokines such as IL-17A, IL-17F, IFN-γ, TNF-α, IL-22, IL-23, CXCL2, CXCL3 and CXCL9, alleviates Imiquimod (HY-B0180)-induced psoriasis in mouse model.
    Paeoniflorin-6′-O-benzene sulfonate
  • HY-P991408
    DLX-105
    		Inhibitor
    DLX-105 is a human monoclonal antibody (mAb) targeting TNFSF2/TNFa. DLX-105 reduces skin epidermal thickness and the expression of K16 and Ki67. DLX-105 down-regulates the mRNA levels of IL-17, TNF-α, IL-23p19, IL-12p40, and IFN-γ. DLX-105 can be used in psoriasis research.
    DLX-105
  • HY-P991409
    GSK2800528
    		Inhibitor
    GSK2800528 is a human monoclonal antibody (mAb) targeting TNFSF2/TNFa. GSK2800528 can be used in inflammation and psoriasis research.
    GSK2800528
  • HY-171468
    CC-1069
    		Inhibitor
    CC-1069, a structural analog of thalidomide (HY-14658), is a TNF-α inhibitor that inhibits endothelial. CC-1069 can be used to study angiogenesis-dependent tumors such as gliomas.
    CC-1069
  • HY-P991473
    hCBE-11
    		Inhibitor
    hCBE-11 is a human monoclonal antibody (mAb) targeting TNFRSF3. hCBE-11 can be used in solid tumors research. Recommended isotype control: Human IgG1 kappa, Isotype Control (HY-P99001).
    hCBE-11
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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