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Relationship: 1813

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Blocking of IL-1R leads to Impaired IL-1 signaling

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Blocking of IL-1R

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Impaired IL-1 signaling

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

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

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

The initial step in IL-1 signal transduction is a ligand-induced conformational change in the first extracellular domain of the IL-1RI that facilitates recruitment of IL-1RacP. Through conserved cytosolic regions called Toll- and IL-1R–like (TIR) domains, the trimeric complex rapidly assembles two intracellular signaling proteins, myeloid differentiation primary response gene 88 (MYD88) and interleukin-1 receptor–activated protein kinase (IRAK) 4. Therefore, the suppression of the binding of IL-1 to IL-1R1 suppresses the recruitment of IL-1RacP, which results in impaired IL-1 signaling.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

IL-1Ra blocks IL-1 signaling:

IL-lra alone at concentrations as high as 1 mg/mL did not induce IL-la, IL-lb, TNFa, or IL-6 synthesis. Suppression of IL-1-induced IL-1, TNFa, or IL-6 synthesis was dose-dependent (P ≦ .0001). At a twofold molar excess, IL-lra inhibited IL-1-induced IL-1 or TNFa synthesis by 50% (P < .01); an equimolar concentration of IL-lra inhibited synthesis of these two cytokines by over 20% (P < .05). A 10-fold molar excess of IL-lra over IL-lb reduced IL-lb-induced IL-la by 95% (P = .01) and IL-la-induced IL-1b by 73% (P < .01). In elutriated monocytes, a 10-fold molar excess of IL-lra reduced IL-lb-induced IL-la by 82% (P < .05), TNFa by 64% (P = .05), and IL-6 by 47% (P < .05). (Granowitz et al., 1992)

Canakinumab (ACZ885, Ilaris):

The antibody binds to human IL-1β with high affinity (about 40 pmol/l). The antibody was found to neutralize the bioactivity of human IL-1β on primary human fibroblasts in vitro 44.6 pmol/l (7.1 ±0.56 ng/ml; n = 6) of ED50. Application of Canakinumab intraperitoneally 2 hours before injecting the IL-1β producing cells completely suppressed joint swelling (0.06 mg/kg of EC50) (Alten et al., 2008).

Primary human fibroblasts are stimulated with recombinant IL-1b or conditioned medium obtained from LPS-stimulated human PBMCs in the presence of various concentrations of Cankinumab or IL-1RA ranging from 6 to 18,000 pM. Supernatant is taken after 16 h stimulation and assayed for IL-6 by ELISA. Canakinumab typically have 1 nM or less of EC50 for inhibition of IL-6 production (Canakinumab Patent Application WO02/16436.)

Rilonacept (IL-1 Trap, Arcalyst):

Incubation of the human MRC5 fibroblastic cell line with IL-1β induces secretion of IL-6. At a constant amount of IL-1β (4 pM), the IC50 of the IL-1 trap is ∼2 pM. Another unique property of the IL-1 trap is that it not only blocks IL-1β, but also blocks IL-1α with high affinity (KD = ∼3 pM; data not shown). The titration curve of IL-1 trap in the presence of 10 pM IL-1β shows an IC50 of 6.5 pM, which corresponds to a calculated KD of 1.5 pM (This affinity is 100 times higher than that of the soluble single component receptor IL-1RI(Economides et al., 2003).

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

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.