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-144737
    Anti-inflammatory agent 15
    		Inhibitor
    Anti-inflammatory agent 15 (compound 29) is a potent antimycobacterial and anti-inflammatory agent. Anti-inflammatory agent 15 inhibits Mtb H37Rv and M299 growth, with MIC50 (minimum inhibitory concentration 50%) of 2.3 and 7.8 μM, respectively. Anti-inflammatory agent 15 inhibits NO through the suppression of iNOS expression, and also inhibited the production of TNF-α and IL-1β. Anti-inflammatory agent 15 can be used for tuberculosis (TB) research.
    Anti-inflammatory agent 15
  • HY-160180
    Glucocorticoid receptor agonist-4 Ala-Ala-Mal
    		Inhibitor
    Glucocorticoid receptor agonist-4 Ala-Ala-Mal (Compound Preparation 9) is an anti-human TNFα antibody-glucocorticoid receptor agonist (GC) conjugate. Glucocorticoid receptor agonist-4 Ala-Ala-Mal can be used in the study of autoimmune and inflammatory diseases.
    Glucocorticoid receptor agonist-4 Ala-Ala-Mal
  • HY-147078
    EJMC-1
    		Inhibitor 99.69%
    EJMC-1 is a moderately potent TNF-α inhibitor with an IC50 value of 42 μM.
    EJMC-1
  • HY-N0619R
    Mulberroside A (Standard)
    		Inhibitor
    Mulberroside A (Standard) is the analytical standard of Mulberroside A. This product is intended for research and analytical applications. Mulberroside A is one of the main bioactive constituent in mulberry (Morus alba L.). Mulberroside A decreases the expressions of TNF-α, IL-1β, and IL-6 and inhibits the activation of NALP3, caspase-1, and NF-κB and the phosphorylation of ERK, JNK, and p38, exhibiting anti-inflammatory antiapoptotic effects. Mulberroside A shows inhibitory activity against mushroom tyrosinase with an IC50 of 53.6 μM.
    Mulberroside A (Standard)
  • HY-159144
    Anti-inflammatory agent 91
    		Inhibitor
    Anti-inflammatory agent 91 (Compound 4o) is an anti-inflammatory agent that can reduce inflammatory cytokines by inhibiting the STAT3 and NF-κB signaling pathways. Anti-inflammatory agent 91 can be used in research to improve skin inflammation associated with psoriasis.
    Anti-inflammatory agent 91
  • HY-N8593
    Undecane
    		Inhibitor ≥98.0%
    Undecane has anti-allergic and anti-inflammatory activities on sensitized rat basophilic leukemia (RBL-2H3) mast cells and HaCaT keratinocytes. In sensitized mast cells, Undecane inhibits degranulation and the secretion of histamine and TNF-α[
    Undecane
  • HY-149331
    TNF-α-IN-11
    		Inhibitor
    TNF-α-IN-11 (Compound 10) is a TNF-α inhibitor with a KD value of 12.06 μM. TNF-α-IN-11 binds to TNF-α and blocks the activation of TNF-α-trigged caspase and NF-κB signaling pathway. TNF-α-IN-11 inhibits the phosphorylation of IκBα, as well as the nuclear translocation of NF κB p65. TNF-α-IN-11 can be used for research of TNF-α-mediated autoimmune diseases.
    TNF-α-IN-11
  • HY-162797
    PDE4-IN-18
    		Inhibitor
    PDE4-IN-18 (compound 1l) is a PDE4 inhibitor (IC50=1.55 μM) with anti-inflammatory activity. PDE4-IN-18 exerts anti-inflammatory effects by reducing excessive immune cell infiltration and intestinal membrane formation, as well as reducing the mRNA expression of pro-inflammatory cytokines (such as TNF-α and IL-6) in synovial tissue. PDE4-IN-18 can be used in the study of rheumatoid arthritis and psoriasis.
    PDE4-IN-18
  • HY-15790H
    (S)-Elobixibat
    		Inhibitor 98.75%
    (S)-Elobixibat is the S enantiomer of Elobixibat (HY-15790). (S)-Elobixibat is an orally effective Apical Sodium-Dependent Bile (IBAT) inhibitor. (S)-Elobixibat decreases LDL cholesterol, increases serum GLP-1, promotes colon motility, and has the potential to treat metabolic syndrome. (S)-Elobixibat can be used to study constipation, dyslipidemia, non-alcoholic hepatitis, and liver tumors.
    (S)-Elobixibat
  • HY-P3149A
    LEESGGGLVQPGGSMK TFA
    LEESGGGLVQPGGSMK TFA, a proteolysis peptide, is a component of Infliximab. LEESGGGLVQPGGSMK TFA can be used for quantitative analysis of Infliximab. Infliximab is a chimeric monoclonal IgG1 antibody that specifically binds to TNF-α.
    LEESGGGLVQPGGSMK TFA
  • HY-W010201R
    Citronellol (Standard)
    		Modulator
    Citronellol (Standard) is the analytical standard of Citronellol. Citronellol (Standard) is an orally active inducer of apoptosis. Citronellol (Standard) can prevent oxidative stress, mitochondrial dysfunction, and apoptosis in the SH-SY5Y cell Parkinson's disease model induced by 6-OHDA by regulating the ROS-NO, MAPK/ERK, and PI3K/Akt signaling pathways. Citronellol (Standard) can induce necroptosis in human lung cancer cells through the TNF-α pathway and accumulation of ROS. Citronellol (Standard) can reduce the levels of LC-3 and p62 to regulate the autophagy pathway, inhibit oxidative stress and neuroinflammation, and thus have neuroprotective effects on Parkinson's rats. Citronellol (Standard) exhibits anti-fungal activity against Trichophyton rubrum by inhibiting ergosterol synthesis.
    Citronellol (Standard)
  • HY-N0635R
    Prim-O-glucosylcimifugin (Standard)
    Prim-O-glucosylcimifugin (Standard) is the analytical standard of Prim-O-glucosylcimifugin. This product is intended for research and analytical applications. Prim-O-glucosylcimifugin exerts anti-inflammatory effects through the inhibition of iNOS and COX-2 expression by through regulating JAK2/STAT3 signaling.
    Prim-O-glucosylcimifugin (Standard)
  • HY-155821
    Anti-inflammatory agent 55
    		Inhibitor
    Anti-inflammatory agent 55 (compound 9j) is a derivative of Coixol and has anti-inflammatory activity. Anti-inflammatory agent 54 inhibits the NF-κB pathway and downregulates the expression of iNOS, TNF-α, IL-6 and IL-1β. Anti-inflammatory agent 54 inhibits LPS-induced nitric oxide (NO) production in RAW264.7 macrophages (IC50: 0.8 μM) and exerts in vivo anti-inflammatory activity in a mouse auricular edema model.
    Anti-inflammatory agent 55
  • HY-18759
    BMS-751324
    		Inhibitor
    BMS-751324 is a p38α MAPK inhibitor. BMS-751324 equips a precursor of carbamyl-methyl linkage, containing esters and phosphate functional groups derived from hydroxyphenylacetic acid (HPA). BMS-751324 effectively inhibits foot swelling and LPS-induced TNFα production in an arthritic rat model.
    BMS-751324
  • HY-P99772
    Onfekafusp alfa
    Onfekafusp alfa (L19TNF) is a homotrimer that forms from engineered peptides for the L19 antibody in scFv format fused to human TNF. Onfekafusp alfa can be used for malignant glioma research.
    Onfekafusp alfa
  • HY-143410
    Anti-inflammatory agent 16
    		Inhibitor
    Anti-inflammatory agent 16 (compound 14), a peptidomimetic, shows potent anti-inflammatory activity. Anti-inflammatory agent 16 reduces TNFα, NO, CD40 and CD86 expression level.
    Anti-inflammatory agent 16
  • HY-N0472R
    Geraniin (Standard)
    		Inhibitor
    Geraniin (Standard) is the analytical standard of Geraniin. This product is intended for research and analytical applications. Geraniin is a TNF-α releasing inhibitor with numerous activities including anticancer, anti-inflammatory, and anti-hyperglycemic activities, with an IC50 of 43 μM.
    Geraniin (Standard)
  • HY-153330
    TNF-α-IN-10
    		Inhibitor
    TNF-α-IN-10 (compound 8a) is a IL-6 and TNF-α inhibitor. TNF-α-IN-10 shows anti-inflammatory activity.
    TNF-α-IN-10
  • HY-162641
    AF-45
    		Inhibitor
    AF-45 inhibits IRAK4 and IRAK1, with IC50s of 128 nM and 1765 nM. AF-45 inhibits the release of IL-6 and TNF-α in macrophages, with IC50s of 0.53-1.54 μM and 0.6-2.75 μM. AF-45 is also an inhibitor for NF-κB/MAPK signaling pathway. AF-45 exhibits anti-inflammatory activities against DSS-induced ulcerative colitis and Lipopolysaccharide (HY-D1056)-induced acute lung injury in mouse model. AF-45 exhibits good pharmacokinetic characteristics in rat models.
    AF-45
  • HY-N1904
    4′-Hydroxywogonin
    		Inhibitor
    4′-Hydroxywogonin (8-Methoxyapigenin), a flavonoid, could be isolated from a variety of plants including Scutellaria barbata and Verbena littoralis. 4′-Hydroxywogonin has anti-inflammatory activity via TAK1/IKK/NF-κB, MAPKs and PI3/AKT signaling pathways. 4′-Hydroxywogonin inhibits angiogenesis by disrupting PI3K/AKT signaling. 4′-Hydroxywogonin inhibits cell proliferation and induces apoptosis.
    4′-Hydroxywogonin
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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