Inhibition, Nuclear factor kappa B (NF-kB)

79-94-7

VEORPZCZECFIRK-UHFFFAOYSA-N

3,3',5,5'-Tetrabromobisphenol A

3,3’,5,5’-Tetrabromobisphenol A (Tetrabromobisphenol A) (Phenol, 4,4'-(1-methylethylidene)bis[2,6-dibromo-) (TBBPA) Phenol, 4,4'-(1-methylethylidene)bis[2,6-dibromo- 2, 2-Bis (4'-hydroxy-3',-5'-dibromophenyl) propane 2,2',6,6'-Tetrabrom-4,4'-isopropylidendiphenol 2,2',6,6'-tetrabromo-4,4'-isopropilidendifenol 2,2',6,6'-tetrabromo-4,4'-isopropylidenediphenol 2,2',6,6'-Tetrabromobisphenol A 2,2-Bis(3,5-dibromo-4-hydroxyphenyl)propane 2,2-Bis(4-hydroxy-3,5-dibromophenyl)propane 3,5,3',5'-Tetrabromobisphenol A 4,4'-(1-Methylethylidene)bis[2,6-dibromophenol] 4,4'-Isopropylidenebis[2,6-dibromophenol] BIS(PHENOL, 2,6-DIBROMO), 4,4'-(1-METHYLETHYLIDENE) BISPHENOL A, TETRABROMO- BISPHENOL, 4,4'-(1-METHYLETHYLIDENE)TETRABROMO- Bromdian Fire Guard 2000 Firemaster BP 4A NSC 59775 Phenol, 4,4'-isopropylidenebis[2,6-dibromo- Saytex CP 2000 Saytex RB 100 Saytex RB 100PC Tetrabromobisphenol A TETRABROMOBISPHENOL-A Tetrabromodian Tetrabromodiphenylolpropane

DTXSID1026081

PR:000001753

PR transcription factor NF-kappa-B subunit

PR:000013058

PR peroxisome proliferator-activated receptor gamma

GO:0007249

GO I-kappaB kinase/NF-kappaB signaling

GO:0035357

GO peroxisome proliferator activated receptor signaling pathway

WIKI decreased

IL-1 receptor antagonist（IL-1Ra）(Anakinra)

2019-06-01T00:37:57

anti-IL-1b antibody (Canakinumab)

2019-06-01T00:38:21

soluble IL-1R (Rilonacept)

2019-06-01T00:38:52

Tetrabromobisphenol A

2017-03-10T00:10:21

2018-07-20T05:36:51

9606

NCBI Homo sapiens

10090

NCBI Mus musculus

10116

NCBI Rattus norvegicus

Inhibition, Nuclear factor kappa B (NF-kB)

Molecular

The NF-κB pathway consists of a series of events including IRAK (IL-1 receptor-associated kinase) signaling, where the transcription factors of the NF-κB family play the key role. The canonical NF-κB pathway can be activated by a range of stimuli, including TNF receptor activation by TNF-a. Upon pathway activation, the IKK complex will be phosphorylated, which in turn phosphorylates IkBa. This NF-κB inhibitor will be K48-linked ubiquitinated and degradated, allowing NF-κB to translocate to the nucleus. There, this transcription factor can express pro-inflammatory and anti-apoptotic genes. Furthermore, negative feedback genes are also transcribed and include IkBa and A20. When the NF-κB pathway is inhibited, its translocation will be delayed (or absent), resulting in less or no regulation of NF-κB target genes. This can be achieved by IKK inhibitors, proteasome inhibitors, nuclear translocation inhibitors or DNA-binding inhibitors (Gupta et al., 2010; Liu et al., 2017). Therefore, inhibition of IL-1R activation suppresses NF-κB.   In addition to the NF-kB pathway, IRAK activates a variety of transcription factors, including Interferon regulatory factor 5 (IRF5), Adaptor protein-1 (AP-1) and cAMP response element binding protein (CREB), resulting in the expression of broad array of inflammatory molecules and apoptosis-related proteins (Jain, 2014).

NF-κB transcriptional activity: Beta lactamase reporter gene assay (Miller et al. 2010) NF-κB transcription: Lentiviral NF-κBGFP reporter with flow cytometry (Moujalled et al. 2012) IκBα phosphorylation: Western blotting (Miller et al. 2010) NF-κB p65 (Total/Phospho) ELISA： ELISA for IL-6, IL-8, and Cox

The binding of sex steroids to their respective steroid receptors directly influences NF-κB signaling, resulting in differential production of cytokines and chemokines (McKay and Cidlowski, 1999; Pernis, 2007). 17b-estradiol regulates pro-inflammatory responses that are transcriptionally mediated by NF‑κB through a negative feedback and/or transrepressive interaction with NF-κB (Straub, 2007). Progesterone suppresses innate immune responses and NF-κB signal transduction reviewed by Klein et al. (Klein and Flanagan, 2016). Androgen-receptor signaling antagonises transcriptional factors NF-κB(McKay and Cidlowski, 1999). Evidence for perturbation of this molecular initiating event by stressor Dex inhibits IL-1β gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-κB/Rel and AP-1 activation (Jeon et al., 2000). Various inhibitors for NF‐κB, such as dimethyl fumarate, curcumin, iguratimod, epigalocathechin gallate (EGCG), and DHMEQ inhibits lLPS-induced NF-κB activation and LPS-induced secretion of IL-1β (McGuire et al., 2016; Mucke, 2012; Peng et al., 2012; Suzuki and Umezawa, 2006; Wang et al., 2020; Wang et al., 2018; Wheeler et al., 2004). TAK-242 (Matsunaga et al., 2011) inhibit TLR4 itself. There are several IRAK4 inhibitors (Lee et al., 2017). These molecules block the upstream signal to NF‐κB activation. IRAK4 has recently attracted attention as a therapeutic target for inflammation and tumor diseases (Chaudhary et al., 2015). LPS treatment induced a significant upregulation of the mRNA and release of IL-1β from retinal microglia. Minocycline inhibited its releases. Thus, minocycline might exert its antiinflammatory effect on microglia by inhibiting the expression and release of IL-1β (Wang et al., 2005). Caspase-1 inhibition reduced the release of IL-1β in organotypic slices exposed to LPS+ATP. Administration of pralnacasan (intracerebroventricular, 50 μg) or belnacasan (intraperitoneal, 25–200 mg/kg) to rats blocked seizure-induced production of IL-1β in the hippocampus, and resulted in a twofold delay in seizure onset and 50% reduction in seizure duration (Ravizza et al., 2006). Belnacasan, an orally active IL-1β converting enzyme/caspase-1 inhibitor, blocked IL-1β secretion with equal potency in LPS-stimulated cells from familial cold urticarial associated symdrome and control subjects (Stack et al., 2005). In LPS-induced acute lung injury (ALI) mice model, LPS induced inflammatory cytokines such as TNF-α, IL-6, IL-13 and IL-1β were significantly decreased by cinnamaldehyde (CA) (Huang and Wang, 2017). The suppressing capacities of six cinnamaldehyde-related compounds were evaluated and compared by using the LPS-primed and ATP-activated macrophages. At concentrations of 25~100 mM, cinnamaldehyde and 2-methoxy cinnamaldehyde dose-dependently inhibited IL-1β secretion (Ho et al., 2018). In vitro, CA decreased the levels of pro-IL-1β and IL-1β in cell culture supernatants, as well as the expression of NLRP3 and IL-1β mRNA in cells. In vivo, CA decreased IL-1β production in serum. Furthermore, CA suppressed LPS-induced NLRP3, p20, Pro-IL-1β, P2X7 receptor (P2X7R) and cathepsin B protein expression in lung, as well as the expression of NLRP3 and IL-1β mRNA (Xu et al., 2017). IL-1Ra binds IL-1R but does not initiate IL-1 signal transduction (Dripps et al., 1991). Recombinant IL-1Ra (anakinra) is fully active in blocking the IL-1R1, and therefore, the biological activities of IL-1α and IL-1β. The binding of IL-1α and IL-1β to IL-1R1 can be suppressed by soluble IL-1R like rilonacept (Kapur and Bonk, 2009). The binding of IL-1β to IL-1R1 can be inhibited by anti-IL-1β antibody (canakinumab and gevokizumab) (Church and McDermott, 2009) (Roell et al., 2010). IL-1 is known to mediates autoinflammatory syndrome, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever. Blocking of binding of IL-1 to IL-1R1 by anakinra, canakinumab, and rilonacept have been already used to treat these autoinflammatory syndrome associated with overactivation of IL-1 signaling (Quartier, 2011). Dex inhibits IL-1β gene expression in LPS-stimulated RAW 264.7 cells by blocking NF‐κB/Rel and AP-1 activation (Jeon et al., 2000). Inhibition of IL-1 binding to IL-1R or the decreased production of IL-1b leads to the suppression of IL-1R signaling leading to NF‐κB activation.

UBERON:0002405

UBERON immune system

CL:0000084

CL T cell

High Unspecific

High

All life stages

High High High

Chaudhary, D., Robinson, S., Romero, D.L. (2015), Recent advances in the discovery of small molecule inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4) as a therapeutic target for inflammation and oncology disorders. J Med Chem 58: 96-110, 10.1021/jm5016044 Church, L.D., McDermott, M.F. (2009), Canakinumab, a fully-human mAb against IL-1beta for the potential treatment of inflammatory disorders. Curr Opin Mol Ther 11: 81-89, Dripps, D.J., Brandhuber, B.J., Thompson, R.C., et al. (1991), Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem 266: 10331-10336, Gupta, S.C., Sundaram, C., Reuter, S., et al. (2010), Inhibiting NF-kappaB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta 1799: 775-787, 10.1016/j.bbagrm.2010.05.004 Ho, S.C., Chang, Y.H., Chang, K.S. (2018), Structural Moieties Required for Cinnamaldehyde-Related Compounds to Inhibit Canonical IL-1beta Secretion. Molecules 23, 10.3390/molecules23123241 Huang, H., Wang, Y. (2017), The protective effect of cinnamaldehyde on lipopolysaccharide induced acute lung injury in mice. Cell Mol Biol (Noisy-le-grand) 63: 58-63, 10.14715/cmb/2017.63.8.13 Jain, A., Kaczanowska, S., Davila, E. (2014), IL-1 receptor-associated kinase signaling and its role in inflammation, cancer, progression, and therapy resistance. Frontiers in Immunology 5:553. Jeon, Y.J., Han, S.H., Lee, Y.W., et al. (2000), Dexamethasone inhibits IL-1 beta gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-kappa B/Rel and AP-1 activation. Immunopharmacology 48: 173-183, Kapur, S., Bonk, M.E. (2009), Rilonacept (arcalyst), an interleukin-1 trap for the treatment of cryopyrin-associated periodic syndromes. P t 34: 138-141, Klein, S.L., Flanagan, K.L. (2016), Sex differences in immune responses. Nat Rev Immunol 16: 626-638, 10.1038/nri.2016.90 Lee, K.L., Ambler, C.M., Anderson, D.R., et al. (2017), Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoli ne-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design. J Med Chem 60: 5521-5542, 10.1021/acs.jmedchem.7b00231 Liu, T., Zhang, L., Joo, D., et al. (2017), NF-kappaB signaling in inflammation. Signal Transduct Target Ther 2, 10.1038/sigtrans.2017.23 Matsunaga, N., Tsuchimori, N., Matsumoto, T., et al. (2011), TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Mol Pharmacol 79: 34-41, 10.1124/mol.110.068064 McGuire, V.A., Ruiz-Zorrilla Diez, T., Emmerich, C.H., et al. (2016), Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation. Sci Rep 6: 31159, 10.1038/srep31159 McKay, L.I., Cidlowski, J.A. (1999), Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr Rev 20: 435-459, 10.1210/edrv.20.4.0375 Mucke, H.A. (2012), Iguratimod: a new disease-modifying antirheumatic drug. Drugs Today (Barc) 48: 577-586, 10.1358/dot.2012.48.9.1855758 Peng, H., Guerau-de-Arellano, M., Mehta, V.B., et al. (2012), Dimethyl fumarate inhibits dendritic cell maturation via nuclear factor kappaB (NF-kappaB) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen stress-activated kinase 1 (MSK1) signaling. J Biol Chem 287: 28017-28026, 10.1074/jbc.M112.383380 Pernis, A.B. (2007), Estrogen and CD4+ T cells. Curr Opin Rheumatol 19: 414-420, 10.1097/BOR.0b013e328277ef2a Quartier, P. (2011), Interleukin-1 antagonists in the treatment of autoinflammatory syndromes, including cryopyrin-associated periodic syndrome. Open Access Rheumatol 3: 9-18, 10.2147/oarrr.S6696 Ravizza, T., Lucas, S.M., Balosso, S., et al. (2006), Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia 47: 1160-1168, 10.1111/j.1528-1167.2006.00590.x Roell, M.K., Issafras, H., Bauer, R.J., et al. (2010), Kinetic approach to pathway attenuation using XOMA 052, a regulatory therapeutic antibody that modulates interleukin-1beta activity. J Biol Chem 285: 20607-20614, 10.1074/jbc.M110.115790 Stack, J.H., Beaumont, K., Larsen, P.D., et al. (2005), IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol 175: 2630-2634, Straub, R.H. (2007), The complex role of estrogens in inflammation. Endocr Rev 28: 521-574, 10.1210/er.2007-0001 Suzuki, E., Umezawa, K. (2006), Inhibition of macrophage activation and phagocytosis by a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin. Biomed Pharmacother 60: 578-586, 10.1016/j.biopha.2006.07.089 Wang, A.L., Yu, A.C., Lau, L.T., et al. (2005), Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 47: 152-158, 10.1016/j.neuint.2005.04.018 Wang, F., Han, Y., Xi, S., et al. (2020), Catechins reduce inflammation in lipopolysaccharide-stimulated dental pulp cells by inhibiting activation of the NF-kappaB pathway. Oral Dis 26: 815-821, 10.1111/odi.13290 Wang, Y., Tang, Q., Duan, P., et al. (2018), Curcumin as a therapeutic agent for blocking NF-kappaB activation in ulcerative colitis. Immunopharmacol Immunotoxicol 40: 476-482, 10.1080/08923973.2018.1469145 Wheeler, D.S., Catravas, J.D., Odoms, K., et al. (2004), Epigallocatechin-3-gallate, a green tea-derived polyphenol, inhibits IL-1 beta-dependent proinflammatory signal transduction in cultured respiratory epithelial cells. J Nutr 134: 1039-1044, 10.1093/jn/134.5.1039 Xu, F., Wang, F., Wen, T., et al. (2017), Inhibition of NLRP3 inflammasome: a new protective mechanism of cinnamaldehyde in endotoxin poisoning of mice. Immunopharmacol Immunotoxicol 39: 296-304, 10.1080/08923973.2017.1355377   AOPWiki 2016-11-29T18:41:23

2023-03-02T01:58:01

Diminished survival of naive B lymphocytes

Lower survival B lymphocytes

Cellular

AOPWiki 2025-12-03T12:04:16

2025-12-03T12:04:16

Diminished proliferation of activated B lymphocytes

Cellular

AOPWiki 2025-12-03T12:06:56

2025-12-03T12:06:56

Diminished differentiation of activated B lymphocytes

Cellular

AOPWiki 2025-12-03T12:07:34

2025-12-03T12:07:34

Diminished vaccine response

Individual

AOPWiki 2025-12-03T12:08:31

2025-12-03T12:08:31

Reduced antibody production

Cellular

AOPWiki 2025-12-03T12:10:12

2025-12-03T12:10:12

Activation of specific nuclear receptors, PPAR-gamma activation

Molecular

CL:0000182

CL hepatocyte

AOPWiki 2016-11-29T18:41:28

2017-09-16T10:17:02

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AOPWiki 2025-12-03T12:10:38

2025-12-03T12:10:38

<upstream-id>93727e9d-e131-48a1-a26b-f7eb0c97d3c1</upstream-id> <downstream-id>28fa2202-6093-42d4-a94f-6c4987094d50</downstream-id>

AOPWiki 2025-12-03T12:11:05

2025-12-03T12:11:05

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AOPWiki 2025-12-03T12:11:20

2025-12-03T12:11:20

<upstream-id>db5bc532-dbea-4b8c-b2f3-651db7baae22</upstream-id> <downstream-id>cab01e77-6f2b-4ba7-ada7-acd9eeb7ab96</downstream-id>

AOPWiki 2025-12-03T12:11:35

2025-12-03T12:11:35

<upstream-id>cab01e77-6f2b-4ba7-ada7-acd9eeb7ab96</upstream-id> <downstream-id>8ea18fd7-98e5-4377-aa84-b1932646f594</downstream-id>

AOPWiki 2025-12-03T12:11:45

2025-12-03T12:11:45

<upstream-id>7daf6282-3d0e-4670-aea1-a62fe25518e0</upstream-id> <downstream-id>28fa2202-6093-42d4-a94f-6c4987094d50</downstream-id>

AOPWiki 2025-12-03T12:11:57

2025-12-03T12:11:57

<upstream-id>28fa2202-6093-42d4-a94f-6c4987094d50</upstream-id> <downstream-id>db5bc532-dbea-4b8c-b2f3-651db7baae22</downstream-id>

AOPWiki 2025-12-03T12:12:06

2025-12-03T12:12:06

<upstream-id>ae5e0089-8506-44a5-8212-dc0d2ef4e12d</upstream-id> <downstream-id>93727e9d-e131-48a1-a26b-f7eb0c97d3c1</downstream-id>

AOPWiki 2026-01-16T11:46:51

2026-01-16T11:46:51

PPARgamma activation leads to a diminished vaccine response

Léo SPORTES-MILOT

BY-SA

2.7

Activation of peroxisome proliferator-activated receptor gamma (PPARγ) by exogenous ligands, such as environmental pollutants including certain PFAS, or endogenous ligands produced by cellular metabolism, is now recognized as a factor in modulating the immune response. The TDI of 4.4 ng/kg/bw (for PFAS) has been established based on its immunotoxic effect. However, the mechanistic understanding of the action of PFAS on the immune system has not really been studied in the literature. This is especially relevant, given evidence from cohort studies showing that PFAS exposure correlates with weaker responses to childhood vaccines, such as diphtheria and tetanus, raising public health implications for vaccination programs in contaminated areas. In this AOP proposal, we choose the MIE PPARγ activation. It induces the expression of genes involved in anti-inflammatory pathways, including the inhibition of NF-κB signaling in B lymphocytes, a crucial subset of cells, particularly for the adaptive immune response. Thus, constructing an Adverse Outcome Pathway (AOP) linking PPARγ activation to diminished vaccine response via NF-κB inhibition in B cells highlights the importance of interactions between environmental factors, B lymphocyte regulation, and adaptive immunity, a novel aspect that remains underexplored in AOPwiki.

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<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

AOPWiki 2025-12-03T10:28:49

2026-01-16T11:46:51