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-P991155
    Ramantamig
    		Inhibitor
    Ramantamig (JNJ-79635322) is a humanized monoclonal antibody targeting human CD3ε, GPRC5D, and TNFRSF17 (BCMA). Ramantamig binds to BCMA and GPRC5D on multiple myeloma cells, binds to CD3ε on T cells, forms immunological synapses, and enables T-cell-mediated cytotoxicity. Ramantamig activates T cells concomitantly with inducing myeloma cell cytotoxicity, with no nonspecific T-cell activation in the absence of target myeloma cells. Ramantamig carries mutations to reduce interaction with Fc receptors and disrupt protein A binding of monomeric and homodimerized chains. Ramantamig can be used for the research of multiple myeloma.
    Ramantamig
  • HY-107390A
    AX-024 hydrochloride
    		Inhibitor 99.23%
    AX-024 hydrochloride is an orally available, first-in-class inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation with an IC50 ~1 nM. AX-024 hydrochloride modulates cell signaling by targeting SH3 domains. AX-024 hydrochloride has low-acute toxicity and high potency and selectivity, and strongly inhibit the production of IL-6, TNF-α, IFN-γ, IL-10 and IL-17A.
    AX-024 hydrochloride
  • HY-P99167
    Lucatumumab
    		Inhibitor ≥99.0%
    Lucatumumab (HCD122) is a fully human anti-CD40 antagonist monoclonal antibody, which blocks CD40/CD40L-mediated signaling. Lucatumumab efficiently mediates antibody-dependent cell-mediated cytotoxicity (ADCC) and clearance of tumor cells, can be used for refractory lymphomas, CLL and multiple myeloma research.
    Lucatumumab
  • HY-P99701
    Letolizumab
    		Inhibitor
    Letolizumab (BMS-986004) is a monoclonal antibody targeting CD40L, which is produced to express mutant IgG1 lacking effector function, including Fc binding and complement fixation. Letolizumab reduces rejection, thromboembolism and prolongs the survival time.
    Letolizumab
  • HY-P990742
    Givastomig
    		Inhibitor 98.556%
    Givastomig (ABL111, TJ033721) is a bispecific antibody (BsAb) inhibitor. Givastomig can specifically binds to Claudin18.2 (CLDN 18.2) on the surface of cancer cells and 4-1BB (CD137, TNFRSF9) on the surface of activated T cells and natural killer (NK) cells. Givastomig is engineered to contain a single Fc-domain mutation (asparagine to alanine) to eliminate Fc-effector function. Givastomig-bound cell lines expressing a range of CLDN18.2 levels with high affinity and induced 4-1BB activation only in the context of CLDN18.2 binding. Givastomig can be used for the study of colon carcinoma.
    Givastomig
  • HY-141582
    Ceramide 3
    		Inhibitor 98.0%
    Ceramide 3 (N-Stearoyl phytosphingosine) is an orally active major component of intercellular lipids in the stratum corneum of the skin, and belongs to the ceramide family. Ceramide 3 inhibits c-jun and NF-κB activation induced by Histamine (HY-B1204), and suppresses the expression of IL-4 and TNF-α. Ceramide 3 inhibits scratching behavior and vascular permeability in mice, and exhibits antihistamine effects in guinea pig ileum. Ceramide 3 improves skin barrier function, reduces transepidermal water loss, erythema and the number of circulating epidermal cells, and accelerates barrier repair of irritated or dysfunctional skin.
    Ceramide 3
  • HY-126066
    (-)-Syringaresinol
    		Inhibitor 99.93%
    (-)-Syringaresinol is an orally active isomer of syringaresinol (HY-N8307) found in Annona Montana. (-)-Syringaresinol exhibits antioxidant, anti-inflammatory, and anticancer activities. (-)-Syringaresinol can alleviate ulcerative colitis via the PI3K-Akt/MAPK/Wnt signaling pathway. (-)-Syringaresinol inhibits HL-60 cell proliferation by arresting the G1 phase and inducing apoptosis. (-)-Syringaresinol inhibits LPS (HY-D1056)-induced microglial activation by downregulating the NF-κB p65 signaling pathway and its interaction with ERβ, exerting anti-neuroinflammatory effects.
    (-)-Syringaresinol
  • HY-B0898
    Ceftiofur sodium
    		Inhibitor 98.02%
    Ceftiofur sodium is a cell wall synthesis inhibitor that targets bacterial penicillin-binding proteins (PBPs) and has anti-inflammatory effects in endotoxemia. Ceftiofur sodium exerts bactericidal effects by inhibiting the synthesis of bacterial cell wall peptidoglycan, leading to bacterial cell lysis. Ceftiofur sodium also inhibits the activation of NF-κB and MAPKs, thereby reducing the secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6.
    Ceftiofur sodium
  • HY-171658
    R1-ICR-5
    		Inhibitor 98.73%
    R1-ICR-5 is a highly selective RIPK1 PROTAC degrader. Mediated by VHL, R1-ICR-5 induces the degradation of RIPK1, which in turn dysregulates the TNFR1 and TLR3/4 signaling hubs, enhances the signaling outputs of NF-κB, MAPK and IFN, and simultaneously promotes RIPK3 activation and necroptosis (necroptosis). R1-ICR-5 can be used in the research of triple-negative breast cancer and skin inflammation.
    R1-ICR-5
  • HY-102040
    Hispidol
    		Inhibitor 98.30%
    Hispidol ((Z)-Hispidol) is a potential therapeutic for inflammatory bowel disease; inhibits TNF-α induced adhesion of monocytes to colon epithelial cells with an IC50 of 0.50 μM.
    Hispidol
  • HY-P990994
    Emunkitug
    		Inhibitor 99.09%
    HY-P990994 is an TNFRSF1B-targeting IgG1κ type humanized antibody, the recommed isotype control is Human IgG1 kappa, Isotype Control (HY-P99001).
    Emunkitug
  • HY-P990095
    Vonsetamig
    		Inhibitor
    Vonsetamig (REGN5459) is a human bispecific antibody targeting BCMA and CD3. Vonsetamig triggers T-cell activation, induces plasma cell depletion, and triggers low-level cytokine release. Vonsetamig can be used for the research of relapsed/refractory multiple myeloma.
    Vonsetamig
  • HY-112275
    TNF-α-IN-1
    		Inhibitor 99.20%
    TNF-α-IN-1 (Compound I-7) is a TNF-α inhibitor. TNF-α-IN-1 can be studied in research for cancers, heart disease, autoimmune disease and infections.
    TNF-α-IN-1
  • HY-B0513
    Methylthiouracil
    		Inhibitor 98.0%
    Methylthiouracil is an antithyroid agent. Methylthiouracil suppresses the production TNF-α and IL-6, and the activation of NF-κB and ERK1/2.
    Methylthiouracil
  • HY-N7102
    Ceftiofur
    		Inhibitor 99.81%
    Ceftiofur is a cell wall synthesis inhibitor that targets bacterial penicillin-binding proteins (PBPs) and has anti-inflammatory effects in endotoxemia. Ceftiofur exerts bactericidal effects by inhibiting the synthesis of bacterial cell wall peptidoglycan, leading to bacterial cell lysis. Ceftiofur also inhibits the activation of NF-κB and MAPKs, thereby reducing the secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6.
    Ceftiofur
  • HY-110036A
    GW405833 hydrochloride
    		Inhibitor 99.59%
    GW405833 (L768242) hydrochloride is a potent, selective cannabinoid receptor 2 (CB2) agonist. GW405833 has EC50 and Ki values ​​of 0.65 nM and 3.92 nM for CB2, and EC50 and Ki values ​​of 16.1 μM and 4772 nM for CB1. GW405833 hydrochloride also exhibits non-competitive CB1 antagonist, exerting its analgesic effect through a CB1 receptor (rather than CB2) dependent mechanism. GW405833 hydrochloride can significantly inhibit the production of cAMP stimulated by Forskolin (HY-15371). GW405833 hydrochloride inhibits glycolysis by down-regulating HIF-1α, thereby alleviating acute liver failure (ALF).
    GW405833 hydrochloride
  • HY-163102
    IA-14069
    		Inhibitor 99.93%
    IA-14069 is an orally active tumor necrosis factor-α (TNF-α) inhibitor. IA-14069 binds directly to TNF-α and TNF-α-triggered signaling (p-IκBα and NF-κB p65) activities. Additionally, IA-14069 exerts a suppressive effect on Dextran sodium sulfate (HY-116282C) (DSS)-induced colitis. IA-14069 can be used for the research of Rheumatoid arthritis (RA) and inflammatory bowel disease (IBD).
    IA-14069
  • HY-W753791
    (±)-Perillaldehyde
    		Inhibitor
    (±)-Perillaldehyde has an antidepressant effect by modulating the olfactory nervous system in a mouse model of stress-induced depression. (±)-Perillaldehyde also has anti-inflammatory activity, inducing JNK activation in RAW264.7 cells and inhibiting the expression of TNF-α, with an IC50 of 171.7 μM.
    (±)-Perillaldehyde
  • HY-P99393
    Tavolixizumab
    		Inhibitor 99.66%
    Tavolixizumab (MEDI 0562; Tavolimab) is a human monoclonal antibody to TNFRSF4 (TNF receptor superfamily member 4) for use in cancer immunology research.
    Tavolixizumab
  • HY-P99605
    Cinrebafusp alfa
    		Inhibitor 98.53%
    Cinrebafusp alfa (PRS 343) is a high affinity CD137/HER2 bispecfic anticalin-based drug. Cinrebafusp alfa binds to recombinant human HER2 (Kd=0.3 nM) and human monomeric CD137 (4-1BB; Kd=5 nM). Cinrebafusp alfa facilitates T-cell costimulation by tumor-localized, HER2-dependent 4-1BB clustering and activation, further enhancing T-cell receptor-mediated activity and leading to tumor destruction. Cinrebafusp alfa has the potential for HER2+ solid tumors research.
    Cinrebafusp alfa
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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