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-B0513R
    Methylthiouracil (Standard)
    		Inhibitor
    Methylthiouracil (Standard) is the analytical standard of Methylthiouracil. This product is intended for research and analytical applications. Methylthiouracil is an antithyroid agent. Methylthiouracil suppresses the production TNF-α and IL-6, and the activation of NF-κB and ERK1/2.
    Methylthiouracil (Standard)
  • HY-N12042
    Taxamairin B
    		Inhibitor
    Taxamairin B is a potent anti-inflammatory agent. Taxamairin B decreases proinflammatory cytokines (TNF-α, IL-1β and IL-6) expression and the production of NO and ROS in LPS-induced RAW264.7 cells. Taxamairin B exhibits significant protective effects in LPS-induced acute lung injury in mice.
    Taxamairin B
  • HY-147697
    LSD1-IN-21
    		Inhibitor
    LSD1-IN-21 (compound 5a) is a potent and BBB-penetrated LSD1 (Lysine specific demethylase-1) inhibitor, with an IC50 of 0.956 µM. LSD1-IN-21 significantly reduces the pro-inflammatory cytokine TNF-α. LSD1-IN-21 shows good anticancer and anti-inflammatory activity.
    LSD1-IN-21
  • HY-N8593S
    Undecane-d24
    Undecane-d24 is the deuterium labeled Undecane[1]. 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[2].
    Undecane-d<sub>24</sub>
  • HY-160434
    TNF-α-IN-13
    		Inhibitor
    TNF-α-IN-13 is a potent TNFα inhibitor with an IC50 of <0.6 μM. TNF-α-IN-13 has antiinflammatory properties (WO2001072735A2; example 6).
    TNF-α-IN-13
  • HY-P990778
    Xirestomig
    Xirestomig is an anti-TNFRSF9/CD274 monoclonal antibody.
    Xirestomig
  • HY-N0267R
    Hypaconitine (Standard)
    		Inhibitor
    Hypaconitine (Standard) is the analytical standard of Hypaconitine. This product is intended for research and analytical applications.
    Hypaconitine (Standard)
  • HY-N3364
    Lucidone
    		Inhibitor
    Lucidone, an anti-inflammatory agent that can be isolated from the fruit of Lindera erythrocarpa Makino. Lucidone inhibits LPS-induced NO and PGE2 production in RAW 264.7 mouse macrophages. Lucidone also decreases TNF-α secretion, iNOS and COX-2 expression. Lucidone prevents NF-κB translocation and inhibits JNK and p38MAPK signals. Lucidone also has inhibitory activity against Dengue virus (DENV) (EC50=25 μM).
    Lucidone
  • HY-160435
    TNF-α-IN-14
    		Inhibitor
    TNF-α-IN-14 is a potent and selective TNFα inhibitor with an IC50 value of 1.1 µM. TNF-α-IN-14 shows antiinflammatory properties (WO2001072735A2; compound 12).
    TNF-α-IN-14
  • HY-B1201R
    Tiratricol (Standard)
    		Inhibitor
    Tiratricol (Standard) is the analytical standard of Tiratricol. This product is intended for research and analytical applications. Tiratricol is an orally available thyroid hormone analog that inhibits pituitary thyroid-stimulating hormone secretion. Tiratricol is an intracellular toxin neutralizer that inhibits LPS and lipid A cytotoxicity with IC50s of 20 μM and 32 μM, respectively. Tiratricol reduces TNF production in lipopolysaccharide-stimulated macrophages. Tiratricol also has antiviral activity and is an inhibitor of yellow fever virus (Flavivirus). It can bind to the RdRp domain of the viral NS5 protein to hinder YFV replication..
    Tiratricol (Standard)
  • HY-N0509R
    Astilbin (Standard)
    		Inhibitor
    Astilbin (Standard) is the analytical standard of Astilbin. This product is intended for research and analytical applications. Astilbin is a flavonoid compound and enhances NRF2 activation. Astilbin also suppresses TNF-α expression and NF-κB activation.
    Astilbin (Standard)
  • HY-12085S2
    (Rac)-Apremilast-d5
    (Rac)-Apremilast-d5 is a deuterium labeled (R)-Apremilast. (R)-Apremilast ((R)-CC-10004) is a enantiomer of Apremilast[1].
    (Rac)-Apremilast-d<sub>5</sub>
  • HY-151188
    DHU-Se1
    		Inhibitor
    DHU-Se1 is a potent anti-inflammatory agent. DHU-Se1 can stimulate macrophages to release the reactive selenium compound and reduce the expression of cellular inflammatory factors (eg: iNOS and TNF-α). DHU-Se1 alleviate the process of inflammation by blocking the polarization of macrophages from M0 to M1.
    DHU-Se1
  • HY-P99775
    Placulumab
    		Inhibitor
    Placulumab (ART621) is an anti-TNF α monoclonal antibody. Placulumab has anti-inflammatory activity and has potential applications in inflammatory diseases such as arthritis.
    Placulumab
  • HY-N2119R
    Sciadopitysin (Standard)
    Sciadopitysin (Standard) is the analytical standard of Sciadopitysin. This product is intended for research and analytical applications. Sciadopitysin is a type of biflavonoids in leaves from ginkgo biloba. Sciadopitysi inhibits RANKL-induced osteoclastogenesis and bone loss by inhibiting NF-κB activation and reducing the expression of c-Fos and NFATc1.
    Sciadopitysin (Standard)
  • HY-155820
    Anti-inflammatory agent 54
    		Inhibitor
    Anti-inflammatory agent 54 (compound 9c) 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: 2.4 μM) and exerts in vivo anti-inflammatory activity in a mouse auricular edema model.
    Anti-inflammatory agent 54
  • HY-148908
    TNF-α-IN-8
    		Inhibitor
    TNF-α-IN-8 (compound I-42) is a TNF-α inhibitor. TNF-α-IN-8 is an isoindole-imide compound. TNF-α-IN-8 can be used for the research of cancer, heart disease, osteoporosis, inflammatory, allergic and autoimmune diseases. TNF-α-IN-8 is a click chemistry reagent, it contains an Azide group and can undergo copper-catalyzed azide-alkyne cycloaddition reaction (CuAAc) with molecules containing Alkyne groups. It can also undergo strain-promoted alkyne-azide cycloaddition (SPAAC) reactions with molecules containing DBCO or BCN groups.
    TNF-α-IN-8
  • HY-15509
    Semapimod
    		Inhibitor
    Semapimod, an inhibitor of proinflammatory cytokine production, can inhibit TNF-α, IL-1β, and IL-6. Semapimod inhibits TLR4 signaling (IC50≈0.3 μM). Semapimod inhibits p38 MAPK and nitric oxide production in macrophages. Semapimod has potential in a variety of inflammatory and autoimmune disorders.
    Semapimod
  • HY-P990710
    Acimtamig
    Acimtamig is an anti-TNFRSF8/FCGR3A monoclonal antibody.
    Acimtamig
  • HY-P99692
    Lenercept
    		Inhibitor
    Lenercept (Ro 45-2081) is a recombinant fusion protein that consists of the soluble TNF-receptor (p55) linked to the Fc portion of human IgG1.
    Lenercept
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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