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-N19420
    Theasinensin C
    		Inhibitor
    Theasinensin C is an orally effective renin inhibitor and gut microbiota modulator, with an IC50 of 40.21 μM against renin activity. Theasinensin C selectively enriches Akkermansia muciniphila in the gut microbiota, enhances the Akkermansia muciniphila-mediated hydrolysis of the PTS domain of mucin, drives the accumulation of luminal glutamine and serine, and regulates the gut-kidney-liver glutamine/serine metabolic signaling pathway to promote creatine biosynthesis. Theasinensin C improves cognitive function, reduces pro-inflammatory cytokines, alleviates neuropathological changes and restores intestinal barrier integrity. Theasinensin C can be used in research related to hypertension and neuroinflammation induced by high-fructose diet.
    Theasinensin C
  • HY-P992479
    UBP1213
    		Inhibitor
    UBP1213 is a monoclonal antibody targeting TNFSF13B/BAFF/CD257.
    UBP1213
  • HY-147141B
    HS-276 formic
    		Inhibitor
    HS-276 formic is an orally active, potent and highly selective TAK1 inhibitor, with a Ki of 2.5 nM. HS-276 formic 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 formic reduces the expression of TNF, IL-6, and IL-1β. HS-276 formic can be used for rheumatoid arthritis (RA) research.
    HS-276 formic
  • HY-160436
    TNF-α-IN-15
    		Inhibitor
    TNF-α-IN-15 is a TNF-α inhibitor. TNF-α-IN-15 can decrease the TNF-α blood levels.
    TNF-α-IN-15
  • HY-125740R
    Malvidin-3-glucoside chloride (Standard)
    		Inhibitor
    Malvidin-3-glucoside (Malvidin-3-O-glucoside; Oenin) chloride (Standard) is the analytical standard of Malvidin-3-glucoside chloride (HY-125740). This product is intended for research and analytical applications. Malvidin-3-glucoside chloride is an orally active inhibitor of the NF-κB pathway, which blocks inflammatory responses induced by TNF-α, reduces IκB-α degradation and p65 nuclear translocation, and upregulates endothelial nitric oxide synthase eNOS to increase NO production. Malvidin-3-glucoside chloride exerts anti-inflammatory and antioxidant effects by inhibiting pro-inflammatory molecules such as MCP-1, ICAM-1, and IL-6, and regulating intestinal microorganisms and metabolites, while protecting endothelial cells and improving intestinal microecological dysbiosis under inflammatory conditions. Malvidin-3-glucoside chloride can be used to study chronic inflammatory-related diseases such as atherosclerosis and inflammatory bowel disease, and has the potential to prevent vascular inflammation and improve intestinal health.
    Malvidin-3-glucoside chloride (Standard)
  • HY-N17821
    Butrin
    		Inhibitor
    Butrin is a compound found in Butea monosperma flowers. Butrin reduces expression of SIRT1, AURKB, cyclin D1, pAKT, GSK-3β, β-catenin, and TGF-3β expression, enhances apoptosis and ROS production in cancer cells. Butrin downregulates Wnt and NF-κB signaling, mitigates oxidative stress, reduces proinflammatory cytokine (TNF-α, IL-6 and IL-8) production and suppresses neuroinflammation. Butrin inhibits IKK enzyme activity. Butrin can be used for the researches of colorectal cancer, Alzheimer’s disease, and rheumatoid arthritis.
    Butrin
  • HY-N9867
    Gnetifolin E
    		Inhibitor
    Gnetifolin E is a resveratrol trimer derivative that can be isolated from Gnetum brunonianum. Gnetifolin E has anti-inflammatory activity, and inhibits TNF-α.
    Gnetifolin E
  • HY-177305
    Anti-inflammatory agent 105
    		Inhibitor
    Anti-inflammatory agent 105 (Compound 12) is an anti-inflammatory compound. The IC50 of Anti-inflammatory agent 105 for the inhibition of TNF-α synthesis and release in the human macrophage cell line U937 is 0.124 nM.
    Anti-inflammatory agent 105
  • HY-153329
    TNF-α-IN-9
    		Inhibitor
    TNF-α-IN-9 (compound 48) is a analog of NDM-1 inhibitor-3 (HY-150758). TNF-α-IN-9 is a TNF-α inhibitor. TNF-α-IN-9 shows low inhibitory activity.
    TNF-α-IN-9
  • HY-120269
    CAY10512
    		Inhibitor
    CAY10512 is a NF-κB inhibitor. CAY10512 can suppress the upregulation of NF-κB-sensitive proinflammatory miRNAs (miRNA-9, miRNA-125b, miRNA-146a, miRNA-155) in cerebrospinal fluid and extracellular fluid. CAY10512 significantly reduces the release of pro-inflammatory cytokines (such as TNF-α, MCP-1, IL-8, IL-6). CAY10512 can be used for researchs on neuroinflammation, islet transplantation and microRNA regulation.
    CAY10512
  • HY-153952
    Immuno modulator-1
    		Inhibitor
    Immuno modulator-1 (compound 22) inhibits TNFα and IL-2 secretion in human peripheral blood mononuclear cells (hPBMC), with IC50 values of 4.7 and 26 nM, respectively. Immuno modulator-1 shows hERG potassium channel blocking effect, with Inhibitory percentage of 20% at 3 μM.
    Immuno modulator-1
  • HY-P991403
    BC011
    		Inhibitor
    BC011 is a human monoclonal antibody (mAb) targeting TNFRSF1B. BC011 promotes CD8+T cell proliferation and depletes Treg cells, thereby increasing the proportion of effector T cells in the tumor microenvironment. BC011 can be used in tumor Immunity research.
    BC011
  • HY-181708
    PROTAC IRAK4 degrader-14
    		Inhibitor
    PROTAC IRAK4 degrader-14 is an orally active IRAK4 PROTAC degrader with a DC50 of 2.4 nM. PROTAC IRAK4 degrader-14 inhibits proinflammatory responses in multiple cell types including T cells, monocytes and keratinocytes. PROTAC IRAK4 degrader-14 is applicable to research related to psoriasis.
    PROTAC IRAK4 degrader-14
  • HY-128754R
    Monoolein (Standard)
    		Inhibitor
    Monoolein is a biocompatible lipid molecule that can be used as a carrier for bone repair. Monoolein exhibits anti-inflammatory activity by inhibiting the immune response induced by LPS (HY-D1056). It exerts its anti-inflammatory effects by reducing the production of immune response factors such as IL-12 p40, IL-6, and TNF-α, and inhibiting the generation of NO. Monoolein can be used in drug delivery and research in the field of inflammatory diseases .
    Monoolein (Standard)
  • HY-W665882
    Norketotifen
    		Inhibitor
    Norketotifen is the active metabolite of Ketotifen (HY-B0157). Norketotifen exhibits skin anti-inflammatory activity, anti-malarial activity, and antipruritic activity against non-histamine-mediated dog itching in mice. Norketotifen effectively inhibits TNF-α release without causing any sedative side effects. Norketotifen can be used for research on non-sedating anti-inflammatory agents.
    Norketotifen
  • HY-N10454
    Sinulatumolin C
    		Inhibitor
    Sinulatumolin C (compound 3) is an anti-inflammatory agent. Sinulatumolin C has significant TNF-α inhibitory activity with an IC50 value of 2.6 μM.
    Sinulatumolin C
  • HY-P992424
    NMB04
    		Inhibitor
    NMB04 is a recombinant anti-Human CD257 (BAFF) (BLyS) antibody. NMB04 binds with specificity and high affinity to soluble and membrane-bound Blys, and blocks Blys binding to receptors TACI, BCMA, and BR-3. NMB04 can be used for the research of autoimmune diseases.
    NMB04
  • HY-163162
    Anhydro-Ouabain
    		Inhibitor
    Anhydro-Ouabain (compound 20) is a cardiotonic steroid which shows anti-inflammatory and neuroprotective activities and thus can be used in neurological research.
    Anhydro-Ouabain
  • HY-115577
    Mitochonic acid 35
    		Inhibitor
    Mitochonic acid 35 is an IAA analogue with cytoprotective effects.
    Mitochonic acid 35
  • HY-178945
    KOR agonist 7
    		Inhibitor
    KOR agonist 7 (Compound 29) is a highly selective κ-opioid receptor (KOR) agonist with a Ki of 138 nM. KOR agonist 7 shows no activity at μ- and δ-opioid receptors or σ1 receptor, and exhibits extremely low affinity for σ2 receptor (Ki = 2.8 μM). KOR agonist 7 significantly reduces the secretion of pro-inflammatory cytokines such as IL-6, TNF-α, and IFN-γ, while increasing the production of the anti-inflammatory cytokine IL-10. KOR agonist 7 downregulates the expression of the pro-inflammatory M1 macrophage marker CD80 and upregulates the anti-inflammatory M2 macrophage marker CD163. KOR agonist 7 holds potential for applications in analgesia and immune modulation.
    KOR agonist 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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