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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AOP Name Role of event in AOP
IL-1 inhibition MolecularInitiatingEvent

Stressors

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Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens 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, Brandhuber 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-R like rilonacept. The binding of IL-1β to IL-1R1 can be inhibited by anti-IL-1β antibody (anti-IL-1β antibody). (Ref)


How It Is Measured or Detected

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The inhibition can be measured by quantitating phosphorylated NF-kB or the proteins or mRNA of IL-6 and IL-8 and other IL-1–responsive cytokines or COX-2 produced by IL-1 stimulated macrophages or macrophage cell lines in the presence of inhibitors (Ref).


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


Overview for Molecular Initiating Event

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IL-1 is known to mediates autoinflammatory syndrome, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever. The stressors of this MIE, such as Anakinra, Canakinumab, and rilonacept have been already used to treat these autoinflammatory syndrome associated with overactivation of IL-1 signaling (Ref).



IL-1 receptor antagonist(IL-1Ra)(Anakinra), anti-IL-1b antibody (Canakinumab), soluble IL-1R (Rilonacept)

IL-1 receptor antagonistIL-1Ra(Anakinra), anti-IL-1b antibody (Canakinumab), soluble IL-1R (Rilonacept)


References

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1. Dripps, D.J., Brandhuber, B.J., Thompson, R.C., Eisenberg, S.P. (1991). J Biol Chem 266 (16): 10331-6.