To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:1813

Relationship: 1813

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

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

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help

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

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help

Taxonomic Applicability

Select one or more structured terms 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. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) 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

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help
Sex Evidence
Unspecific High

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help
Term Evidence
All life stages High

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. 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 Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help
Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured (see page 40 of the User Handbook for further information).   More help

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-R like rilonacept. The binding of IL-1β to IL-1R1 can also be inhibited by anti-IL-1β antibody (anti-IL-1β antibody). 

IL-1 receptor antagonist(IL-1Ra)was purified in 1990, and the cDNA reported that same year. IL-1Ra binds IL-1R but does not initiate IL-1 signal transduction (Dripps et al., 1991). Recombinant IL-1Ra (generic anakinra) is fully active in blocking the IL-1R1, and therefore, the activities of IL-1α and IL-1β. Anakinra is approved for the treatment of rheumatoid arthritis and cryopyrin-associated periodic syndrome (CAPS). Since its introduction in 2002 for the treatment of rheumatoid arthritis, anakinra has had a remarkable record of safety. However, Fleischmann et al. (Fleischmann et al., 2003)reported that serious infectious episodes were observed more frequently in the anakinra group (2.1% versus 0.4% in the placebo group) and other authors reported the increased susceptibility to bacterial or tuberculosis infection (Genovese et al., 2004; Kullenberg et al., 2016; Lequerre et al., 2008; Migkos et al., 2015). As IL-1 signaling antagonists, two drugs went up to the market, canakinumab (anti-IL-1b antibody) and rilonacept (soluble IL-1R). Several reports described that the administration of these drugs led to increased susceptibility to infection (De Benedetti et al., 2018; Imagawa et al., 2013; Lachmann et al., 2009; Schlesinger et al., 2012). 

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help
Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  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
This sub-section should be used to provide 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?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized 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.

References

List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

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.

Arend, W.P., Welgus, H.G., Thompson, R.C., Eisenberg, S.P., 1990. Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest 85, 1694-1697.

De Benedetti, F., Gattorno, M., Anton, J., Ben-Chetrit, E., Frenkel, J., Hoffman, H.M., Kone-Paut, I., Lachmann, H.J., Ozen, S., Simon, A., Zeft, A., Calvo Penades, I., Moutschen, M., Quartier, P., Kasapcopur, O., Shcherbina, A., Hofer, M., Hashkes, P.J., Van der Hilst, J., Hara, R., Bujan-Rivas, S., Constantin, T., Gul, A., Livneh, A., Brogan, P., Cattalini, M., Obici, L., Lheritier, K., Speziale, A., Junge, G., 2018. Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. N Engl J Med 378, 1908-1919.

Dhimolea, E., 2010. Canakinumab. MAbs 2, 3-13.

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.

Economides, A.N., Carpenter, L.R., Rudge, J.S., Wong, V., Koehler-Stec, E.M., Hartnett, C., Pyles, E.A., Xu, X., Daly, T.J., Young, M.R., Fandl, J.P., Lee, F., Carver, S., McNay, J., Bailey, K., Ramakanth, S., Hutabarat, R., Huang, T.T., Radziejewski, C., Yancopoulos, G.D., Stahl, N., 2003. Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat Med 9, 47-52.

Fleischmann, R.M., Schechtman, J., Bennett, R., Handel, M.L., Burmester, G.R., Tesser, J., Modafferi, D., Poulakos, J., Sun, G., 2003. Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo-controlled trial. Arthritis Rheum 48, 927-934.

Genovese, M.C., Cohen, S., Moreland, L., Lium, D., Robbins, S., Newmark, R., Bekker, P., 2004. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 50, 1412-1419.

Granowitz, E.V., Clark, B.D., Vannier, E., Callahan, M.V., Dinarello, C.A., 1992. Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: I. IL-1 receptor antagonist inhibits IL-1-induced cytokine synthesis and blocks the binding of IL-1 to its type II receptor on human monocytes. Blood 79, 2356-2363.

Imagawa, T., Nishikomori, R., Takada, H., Takeshita, S., Patel, N., Kim, D., Lheritier, K., Heike, T., Hara, T., Yokota, S., 2013. Safety and efficacy of canakinumab in Japanese patients with phenotypes of cryopyrin-associated periodic syndrome as established in the first open-label, phase-3 pivotal study (24-week results). Clin Exp Rheumatol 31, 302-309.

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

Kullenberg, T., Lofqvist, M., Leinonen, M., Goldbach-Mansky, R., Olivecrona, H., 2016. Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes. Rheumatology (Oxford) 55, 1499-1506.

Lachmann, H.J., Kone-Paut, I., Kuemmerle-Deschner, J.B., Leslie, K.S., Hachulla, E., Quartier, P., Gitton, X., Widmer, A., Patel, N., Hawkins, P.N., 2009. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360, 2416-2425.

Lequerre, T., Quartier, P., Rosellini, D., Alaoui, F., De Bandt, M., Mejjad, O., Kone-Paut, I., Michel, M., Dernis, E., Khellaf, M., Limal, N., Job-Deslandre, C., Fautrel, B., Le Loet, X., Sibilia, J., 2008. Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 67, 302-308.

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.

Migkos, M.P., Somarakis, G.A., Markatseli, T.E., Matthaiou, M., Kosta, P., Voulgari, P.V., Drosos, A.A., 2015. Tuberculous pyomyositis in a rheumatoid arthritis patient treated with anakinra. Clin Exp Rheumatol 33, 734-736.

Schlesinger, N., Alten, R.E., Bardin, T., Schumacher, H.R., Bloch, M., Gimona, A., Krammer, G., Murphy, V., Richard, D., So, A.K., 2012. Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions. Ann Rheum Dis 71, 1839-1848.

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.