API

Event: 1570

Key Event Title

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Blocking of IL-1R

Short name

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Blocking of IL-1R

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

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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IL-1α and IL-1β independently bind the type I IL-1 receptor (IL-1R1), which is ubiquitously expressed. 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 (anti-IL-1β antibody)(Church and McDermott, 2009).


How It Is Measured or Detected

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  1. Competitive inhibition binding experiments using 125I-IL-1a to type I IL-1R present on EL4 thymoma cells, 3T3 fibroblasts, hepatocytes, and Chinese hamster ovary cells expressing recombinant mouse type I IL-1R (McIntyre et al., 1991; Shuck et al., 1991).
  2. Measure the ability of the reagent to neutralize the bioactivity of human IL-1β on primary human fibroblasts in vitro(Alten et al., 2008)

Domain of Applicability

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Although sex differences in immune responses are well known (Klein and Flanagan, 2016), there is no reports regarding the sex difference in IL-1 production, IL-1 function or susceptibility to infection as adverse effect of IL-1 blocking agent.  Again, age-dependent difference in IL-1 signaling is not known. 

The IL1B gene is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, rat, and frog (https://www.ncbi.nlm.nih.gov/homologene/481), and the Myd88 gene is conserved in human, chimpanzee, rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog (https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849).

These data suggest that the proposed AOP regarding inhibition of IL-1 signaling is not dependent on life stage, sex, age or species.


Evidence for Perturbation by Stressor



References

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Alten, R., Gram, H., Joosten, L.A., van den Berg, W.B., Sieper, J., Wassenberg, S., Burmester, G., van Riel, P., Diaz-Lorente, M., Bruin, G.J., Woodworth, T.G., Rordorf, C., Batard, Y., Wright, A.M., Jung, T., 2008. The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis. Arthritis Res Ther 10, R67.

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., Eisenberg, S.P., 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.

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.

McIntyre, K.W., Stepan, G.J., Kolinsky, K.D., Benjamin, W.R., Plocinski, J.M., Kaffka, K.L., Campen, C.A., Chizzonite, R.A., Kilian, P.L., 1991. Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody. J Exp Med 173, 931-939.

Quartier, P., 2011. Interleukin-1 antagonists in the treatment of autoinflammatory syndromes, including cryopyrin-associated periodic syndrome. Open Access Rheumatol 3, 9-18.

Shuck, M.E., Eessalu, T.E., Tracey, D.E., Bienkowski, M.J., 1991. Cloning, heterologous expression and characterization of murine interleukin 1 receptor antagonist protein. Eur J Immunol 21, 2775-2780.