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-P991195
    SIM-0235
    		Inhibitor
    SIM-0235 is humanized immunoglobulin G1 (IgG1) monoclonal antibody that targets and inhibits TNFR2, the recommed isotype control is Human IgG1 kappa, Isotype Control (HY-P99001)[1].
    SIM-0235
  • HY-171591
    SIK2-IN-4
    		Inhibitor 99.06%
    SIK2-IN-4 (Compound 4) is a highly selective SIK1/2 inhibitor (IC50s 0.143 and 0.076 μM, respectively). SIK2-IN-4 reduces the phosphorylation of transcription coactivator 3 (CRTC3) by targeting SIK1/2, thereby regulating cAMP response element binding protein (CREB)-dependent transcriptional activity. SIK2-IN-4 inhibits the production of pro-inflammatory cytokines such as TNF (IC50: 0.11 µM), IL-12/23 p40 (IC50: 0.25 µM), and IL-23 (IC50: 0.47 µM), while inducing the expression of the anti-inflammatory cytokine IL-10. SIK2-IN-4 can be used to study intestinal inflammation and other chronic inflammatory diseases.
    SIK2-IN-4
  • HY-P990304
    Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1)
    		Inhibitor
    Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1) is a rat-derived IgG2a κ antibody inhibitor, targeting to mouse 4-1BBL/CD137L. Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1) can block 4-1BB ligand (4-1BBL) and inhibit CD4+ and CD8+ T cells. Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1) can be used for the researches of cancer, infection, inflammation and immunology, such as MC38 tumor, lymphocytic choriomeningitis virus (LCMV) infection and herpetic stromal keratitis (HSK).
    Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1)
  • HY-121309R
    Doxorubicinone (Standard)
    		Inhibitor
    Doxorubicinone (Adriamycin aglycone) (Standard) is the analytical standard of Doxorubicinone. This product is intended for research and analytical applications. Doxorubicinone is the aglycone of the antibiotic Doxorubicin (HY-15142A), i.e., its sugar-free parent nucleus structure. Doxorubicinone does not induce DNA damage or bind to RelA, but still downregulates the expression of pro-inflammatory cytokines (such as TNF, IL-12, etc.) regulated by the NF-κB pathway. Doxorubicinone can be used in sepsis-related research.
    Doxorubicinone (Standard)
  • HY-19667
    BMS-561392
    		Inhibitor
    BMS-561392 (BMS-561392) is a selective ADAM17(TACE) inhibitor. BMS-561392 inhibits TNF-α secretion by regulating signaling pathways such as p44 MAPK and NF-κB. BMS-561392 also affects the survival of central nervous system-related cells including oligodendrocytes and microglia. BMS-561392 promotes microglial apoptosis, enlarges the injury area and exacerbates astrogliosis in a mouse spinal cord injury model. BMS-561392 can be used in research related to spinal cord injury and inflammatory diseases.
    BMS-561392
  • HY-10406A
    Talmapimod hydrochloride
    		Inhibitor
    Talmapimod (SCIO-469) hydrochloride is an orally active and selective inhibitor of p38α MAPK with an IC50 of 9 nM. Talmapimod hydrochloride inhibits the secretion of inflammatory factors (such as TNFα, IL-1β, IL-6, and VEGF) by suppressing the p38α MAPK pathway, and it also inhibits angiogenesis and osteoclast activation. Talmapimod hydrochloride inhibits the growth of multiple myeloma cells and induces apoptosis. Talmapimod hydrochloride can be used to study various hematological malignancies (such as multiple myeloma, myelodysplastic syndrome).
    Talmapimod hydrochloride
  • HY-107909
    Theophylline sodium glycinate
    		Inhibitor
    Theophylline (1,3-Dimethylxanthine) sodium glycinate is a potent phosphodiesterase (PDE) inhibitor, adenosine receptor antagonist, and histone deacetylase (HDAC) activator. Theophylline sodium glycinate inhibits PDE3 activity to relax airway smooth muscle. Theophylline sodium glycinate has anti-inflammatory activity by increase IL-10 and inhibit NF-κB into the nucleus. Theophylline sodium glycinate induces apoptosis. Theophylline sodium glycinate can be used for asthma and chronic obstructive pulmonary disease (COPD) research.
    Theophylline sodium glycinate
  • HY-183934
    Anti-inflammatory agent 99
    		Inhibitor
    Anti-inflammatory agent 99 is a chalcone derivative. Anti-inflammatory agent 99 inhibits LPS (HY-D1056)-induced NF-κB nuclear translocation and suppress the phosphorylation of JNK, ERK, and p38. Anti-inflammatory agent 99 inhibits the expression of cytoinflammatory factors such as TNF-α and IL-6 induced by LPS. Anti-inflammatory agent 99 can be used for the research of LPS-induced septic shock.
    Anti-inflammatory agent 99
  • HY-P99578
    Tanfanercept
    		Inhibitor
    Tanfanercept (HL036337) is an TNF-α receptor fusion protein that targets TNF-α. Tanfanercept is effective in ameliorating corneal erosions in a dry eye (DE) mouse model.
    Tanfanercept
  • HY-P991003
    Ingitamig
    		Inhibitor
    HY-P991003 is an TNFRSF17/KLRK1-targeting (G1_L-κ)_(G1-scFvkh_L-κ) type bispecific antibody.
    Ingitamig
  • HY-176234
    PDE4-IN-28
    		Inhibitor
    PDE4-IN-28 (Compound G1) is a PDE4D inhibitor (IC50: 29 nM). PDE4-IN-28 inhibits the production of TNF-α and NO (IC50: 13.32 and 2.32 μM, respectively). PDE4-IN-28 exhibits anti-inflammatory, antibacterial and analgesic effects in a rat pressure ulcer (PU) model and promotes HUVEC cell migration, thereby accelerating wound healing.
    PDE4-IN-28
  • HY-114908
    CX-659S
    		Inhibitor
    CX-659S is an orally active 5-carboxamide uracil derivative. CX-659S can effectively inhibit lipid peroxidation (IC50 = 5.9 μM). CX-659S can reduce the infiltration of neutrophils and eosinophils. CX-659S inhibits the mRNA expression of pro-inflammatory cytokines IL-1β and TNF-α. CX-659S can be used for research on inflammatory conditions.
    CX-659S
  • HY-149151
    Variegatic acid
    		Inhibitor
    Variegatic acid is a secondary metabolite derived from basidiomycete fungi. Variegatic acid is a PKCβ1 inhibitor with an IC₅₀ of 36.2 μM. Variegatic acid inhibits antigen- or calcium ionophore-induced β-hexosaminidase release (IC₅₀ values of 10.4 μM and 22.2 μM, respectively) and TNF-α secretion (IC₅₀ values of 16.8 μM and 20.1 μM, respectively). Variegatic acid suppresses the enzymatic activity of calcium-activated PKCβ1 and reduces Fe(III) to Fe(II) in a pH-dependent manner, enabling the generation of hydroxyl radicals (·OH) through reaction with H₂O₂, which facilitates the degradation of lignocellulose. Variegatic acid is useful for studying biological degradation and allergic responses.
    Variegatic acid
  • HY-175430
    TNF-α-IN-26
    		Inhibitor
    TNF-α-IN-26 (Compound 18) is a TNF-α inhibitor with an IC50 of 0.10  μM for CSBP ligands. TNF-α-IN-26 inhibits LPS (HY-D1056)-stimulated TNF production in mice model. TNF-α-IN-26 can be used for inflammatory diseases research.
    TNF-α-IN-26
  • HY-P3483
    Maxadilan
    		Inhibitor
    Maxadilan is a specific irreversible PAC1 receptor agonist and a potent vasodilator peptide present in the salivary glands of sand flies. Maxadilan exhibits anti-apoptotic activity in hADSCs. Maxadilan inhibits pro-inflammatory cytokines (TNF-α) and enhances anti-inflammatory mediators (IL-10). Maxadilan can activate leukocytes and inhibit vascular permeability through PAC1 receptors. Maxadilan promotes neural differentiation of human adipose-derived stem cells. Maxadilan can be used to study endotoxin shock, atherosclerosis, and neurodegenerative diseases[1][2][3][4][5].
    Maxadilan
  • HY-160437
    TNF-α-IN-16
    		Inhibitor
    TNF-α-IN-16 is a potent TNFα inhibitor with an IC50 of <0.6 μM. TNF-α-IN-16 has antiinflammatory properties (WO2001072735A2; example 18).
    TNF-α-IN-16
  • HY-W012732R
    Isoquinoline (Standard)
    		Inhibitor
    Isoquinoline (Standard) is the analytical standard of Isoquinoline. This product is intended for research and analytical applications. Isoquinoline is an analog of pyridine. Isoquinoline structural-based alkaloids, such as tropoloisoquinoline, phthalideisoquinoline, and naphthylisoquinoline has anti-cancer activities.
    Isoquinoline (Standard)
  • HY-P990304A
    Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1-Mouse IgG2a)
    		Inhibitor
    Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1-Mouse IgG2a) is a mouse-derived IgG2a κ antibody inhibitor that targets mouse 4-1BBL/CD137L. Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1-Mouse IgG2a) 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 IgG2a. Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1-Mouse IgG2a) reacts with mouse 4-1BB ligand (4-1BBL). Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1-Mouse IgG2a) can be used for the researches of cancer, infection, inflammation and immunology.
    Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1-Mouse IgG2a)
  • HY-P991404
    AMG-228
    		Inhibitor
    AMG-228 is a human IgG1 monoclonal antibody (mAb) targeting TNFRSF18/GITR/CD357. AMG-228 can be used in advanced solid tumors research.
    AMG-228
  • HY-P992435
    OX118
    		Inhibitor
    OX118 is a fully human, ADCC-enhanced monoclonal antibody targeting OX40L, the recommended isotype control is HY-P99001. OX118 blocks OX40L, suppresses effector T-cell proliferation, expands regulatory T-cell populations, and reduces bystander activation across natural killer cells, B cells, and CD14+ monocytes. OX118 can be used for the research of graft-versus-host disease.
    OX118
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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