API

Event: 202

Key Event Title

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Inhibition, Nuclear factor kappa B (NF-kB)

Short name

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Inhibition, Nuclear factor kappa B (NF-kB)

Biological Context

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Level of Biological Organization
Molecular

Cell term

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Cell term
macrophage


Organ term

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Organ term
immune system


Key Event Components

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Process Object Action
I-kappaB kinase/NF-kappaB signaling transcription factor NF-kappa-B subunit decreased

Key Event Overview


AOPs Including This Key Event

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Stressors

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Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI
Rattus norvegicus Rattus norvegicus High NCBI

Life Stages

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Life stage Evidence
All life stages High

Sex Applicability

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Term Evidence
Unspecific High

Key Event Description

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The NF-kB pathway consists of a series of events where the transcription factors of the NF-kB family play the key role. The NF-kB pathway can be activated by a range of stimuli, including TNF receptor activation by TNF-a, or IL-1R1 activation by IL-1a or b. Upon pathway activation, the IKK complex will be phosphorylated, which in turn phosphorylates IkBa. This NF-kB inhibitor will be K48-linked ubiquitinated and degradated, allowing NF-kB to translocate to the nucleus. There, this transcription factor can express pro-inflammatory and anti-apoptotic genes. (Frederiksson 2012). (Gupta et al. 2010).(Huppelschoten 2017).(Liu et al. 2017). Therefore, inhibition of IL-1R1 activation suppresses activation of NF-κB.


How It Is Measured or Detected

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NF-kB transcriptional activity: Beta lactamase reporter gene assay (Miller et al. 2010). NF-kB transcription: Lentiviral NF-kB GFP reporter with flow cytometry (Moujalled et al. 2012)

NF-κB translocation: RelA-GFP reporter assay (Frederiksson 2012) (Huppelschoten 2017)

IκB phosphorylation: Western blotting (Miller et al. 2010)

NF-κB p65 (Total/Phospho) ELISA

ELISA for IL-6, IL-8, and Cox


Domain of Applicability

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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 by Stressor



References

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Frederiksson, L., 2012. TNFalpha-signaling in drug induced liver injury. University of Leiden.

Gupta, S.C. et al., 2010. Inhibiting NF-??B activation by small molecules as a therapeutic strategy. Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, 1799(10–12), pp.775–787. Available at: http://dx.doi.org/10.1016/j.bbagrm.2010.05.004.

Huppelschoten, S., 2017. Dynamics of TNFalpha signaling and drug-related liver toxicity. Leiden University.

Klein, S.L., Flanagan, K.L., 2016. Sex differences in immune responses. Nat Rev Immunol 16, 626-638.

Liu, T. et al., 2017. NF-κB signaling in inflammation. Signal Transduction and Targeted Therapy, 2(March), p.17023. Available at: http://www.nature.com/articles/sigtrans201723.

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.

Miller, S.C. et al., 2010. Identification of known drugs that act as inhibitors of NF-κB signaling and their mechanism of action. Biochemical Pharmacology, 79(9), pp.1272–1280. Available at: http://dx.doi.org/10.1016/j.bcp.2009.12.021.

Moujalled, D.M. et al., 2012. In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-?B, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-?B is required to prevent it. Cell Death and Differentiation, 19(5), pp.808–815. Available at: http://dx.doi.org/10.1038/cdd.2011.151.

Pernis, A.B., 2007. Estrogen and CD4+ T cells. Curr Opin Rheumatol 19, 414-420.

Straub, R.H., 2007. The complex role of estrogens in inflammation. Endocr Rev 28, 521-574.