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-N0604R
    Ginsenoside Rh1 (Standard)
    		Inhibitor
    Ginsenoside Rh1 (Standard) is the analytical standard of Ginsenoside Rh1. This product is intended for research and analytical applications. Ginsenoside Rh1 (Prosapogenin A2) inhibits the expression of PPAR-γ, TNF-α, IL-6, and IL-1β.
    Ginsenoside Rh1 (Standard)
  • HY-159884
    MG-T-19
    		Activator
    MG-T-19 is an effective TIM-3 inhibitor that can suppress the interaction of TIM-3 with PtdSer, CEACAM1, and Gal-9. MG-T-19 can increase the production of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in peripheral blood mononuclear cells (PBMCs) from healthy donors, and enhance the ability of PBMCs to inhibit the proliferation of Kasumi-1 cells (an acute myelogenous leukemia cell line).
    MG-T-19
  • HY-P990738
    Enristomig
    Enristomig is an anti-TNFRSF9/CD274 monoclonal antibody.
    Enristomig
  • HY-157809
    Anti-inflammatory agent 74
    		Inhibitor
    Anti-inflammatory agent 74 (B5) is an anti-inflammatory agent that can inhibit NO, IL-6, and TNF-α, with IC50 values of 10.88 μM and 4.93 μM for NO and IL-6, respectively. Anti-inflammatory agent 74 alleviates acute lung injury (ALI) by regulating inflammatory mediators and inhibiting the MAPK and NF-κB signaling pathways.
    Anti-inflammatory agent 74
  • HY-149816
    Anti-inflammatory agent 41
    		Inhibitor
    Anti-inflammatory agent 41 (13a) significantly inhibit lipopolysaccharide (LPS)-induced expression of the proinflammatory cytokines IL-6 and TNF-α on J774A.1, THP-1 and LX-2 cells, and inhibits the activation of the NF-κB pathway.
    Anti-inflammatory agent 41
  • HY-N10782
    Balanophonin
    		Inhibitor
    Balanophonin is an anti-inflammatory and anti-cancer agent. Balanophonin inhibits microglial activation and neurodegeneration via inhibiting activated microglia-induced apoptosis.
    Balanophonin
  • HY-159516
    Sabialimon P
    Sabialimon P (compound 16) is a NO release inhibitor (IC50=18.12 μM) with anti-inflammatory activity. Sabialimon P significantly reduces the secretion of TNF-α, iNOS, IL-6 and NF-κB and inhibits the expression of COX-2 and NF-κB/p65 in RAW264.7 cells induced by LPS (HY-D1056).
    Sabialimon P
  • HY-N0405R
    Orientin (Standard)
    		Inhibitor
    Orientin (Standard) is the analytical standard of Orientin. This product is intended for research and analytical applications. Orientin is a neuroprotective agentinhibits which has anti-inflammation, anti-oxidative, anti-tumor, and cardio protection properties. Orientin inhibits the levels of IL-6, IL-1β and TNF-α. Orientin increases IL-10 level. Orientin exhibits neuroprotective effect by inhibits TLR4 and NF-kappa B signaling pathway. Orientin can used in study neuropathic pain.
    Orientin (Standard)
  • HY-125025
    SMI 6860766
    		Inhibitor
    SMI 6860766, a small molecule inhibitor of CD40-TRAF6 interaction, improves glucose tolerance, reduces immune cell accumulation in adipose tissue, and reduces AT inflammation.
    SMI 6860766
  • HY-146419
    Anti-inflammatory agent 20
    		Inhibitor
    Anti-inflammatory agent 20 (compound 5a) is a potent inhibitor of NO activity. Anti-inflammatory agent 20 shows anti-inflammatory activity. Anti-inflammatory agent 20 suppresses LPS-induced inflammation via inhibiting the activation of NF-κB and MAPK signaling and thereby reducing IL-6, TNF-α, iNOS, and COX-2 upregulation.
    Anti-inflammatory agent 20
  • HY-168130
    TNF-α/IL-1β-IN-1
    		Inhibitor
    TNF-α/IL-1β-IN-1 (compund 11a) is an anti-inflammatory agent that reduces the expression of TNF-α and IL-1β, inhibits oxidative stress and cardiomyocyte apoptosis, has good activity against septic myocardial injury, and improves myocardial blood supply in vivo.
    TNF-α/IL-1β-IN-1
  • HY-P10850
    PIYLGGVFQ
    		Antagonist
    PIYLGGVFQ is a peptide inhibitor for TNF-α. PIYLGGVFQ inhibits TNF-α-mediated apoptosis, NF-κB nuclear translocation and activation. PIYLGGVFQ exhibits anti-arthritic activity in the CIA mouse model.
    PIYLGGVFQ
  • HY-173290
    PDE4D inhibitor 1
    		Inhibitor
    PDE4-IN-1 is a PDE4 inhibitor with high potency (IC50 : 8.6 nM) and selectivity over other PDE subtypes. PDE4-IN-1 inhibits the release of inflammatory cytokines and chemokines. PDE4-IN-1 greatly restores impaired cAMP-CREB signaling pathway. PDE4-IN-1 inhibits proliferation and promotes differentiation to reverse the formation of psoriasis.
    PDE4D inhibitor 1
  • HY-170686
    BRD4 Inhibitor-38
    		Inhibitor
    BRD4 Inhibitor-38 (Compound 25) is an orally active inhibitor of BRD4 with IC50 values of 3.64 μM and 0.12 μM against BRD4 BD1 and BRD4 BD2, respectively. BRD4 Inhibitor-38 also exhibits anti-inflammatory activity, with an IC50 value of 1.98 μM for inhibiting nitric oxide (NO) production.
    BRD4 Inhibitor-38
  • HY-N0616R
    Trifolirhizin (Standard)
    Trifolirhizin (Standard) is the analytical standard of Trifolirhizin. This product is intended for research and analytical applications. Trifolirhizin is a pterocarpan flavonoid isolated from the roots of Sophora flavescens. Trifolirhizin possesses potent tyrosinase inhibitory activity with an IC50 of 506 μM. Trifolirhizin exhibits potential anti-inflammatory and anticancer activities.
    Trifolirhizin (Standard)
  • 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-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
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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