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Aop: 277

Title

Each AOP should be given a descriptive title that takes the form “MIE leading to AO”. For example, “Aromatase inhibition [MIE] leading to reproductive dysfunction [AO]” or “Thyroperoxidase inhibition [MIE] leading to decreased cognitive function [AO]”. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Impaired IL-1R1 signaling leading to increased susceptibility to infection

Short name

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IL-1 inhibition

Graphical Representation

A graphical summary of the AOP listing all the KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs should be provided. This is easily achieved using the standard box and arrow AOP diagram (see this page for example). The graphical summary is prepared and uploaded by the user (templates are available) and is often included as part of the proposal when AOP development projects are submitted to the OECD AOP Development Workplan. The graphical representation or AOP diagram provides a useful and concise overview of the KEs that are included in the AOP, and the sequence in which they are linked together. This can aid both the process of development, as well as review and use of the AOP (for more information please see page 19 of the Users' Handbook).If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Choose File’ under the “Graphical Representation” heading, which is part of the Summary of the AOP section, to select the file that you have just edited. Files must be in jpeg, jpg, gif, png, or bmp format. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading. To remove a graphical representation file, click 'Remove' and then click 'OK.' Your graphic should no longer be displayed on the AOP page. If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you. Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Be sure to save the diagram as jpeg, jpg, gif, png, or bmp format. Once the diagram is edited to its final state, upload the image file as described above. More help

Click to download graphical representation template

W1siziisijiwmjavmtivmjivnna0cmg1exy0zv8ymdiwmtiyml9bt1bfsuxfms5qcgcixsxbinailcj0ahvtyiisijuwmhg1mdaixv0?sha=d7e7714c18439ab1

Authors

List the name and affiliation information of the individual(s)/organisation(s) that created/developed the AOP. In the context of the OECD AOP Development Workplan, this would typically be the individuals and organisation that submitted an AOP development proposal to the EAGMST. Significant contributors to the AOP should also be listed. A corresponding author with contact information may be provided here. This author does not need an account on the AOP-KB and can be distinct from the point of contact below. The list of authors will be included in any snapshot made from an AOP. More help

Yutaka Kimura (1) Setsuya Aiba (1)

(1) Depertment of Dermatology, Tohoku University Graduate School of Medicine

Corresponding author: Setsuya Aiba

Point of Contact

Indicate the point of contact for the AOP-KB entry itself. This person is responsible for managing the AOP entry in the AOP-KB and controls write access to the page by defining the contributors as described below. Clicking on the name will allow any wiki user to correspond with the point of contact via the email address associated with their user profile in the AOP-KB. This person can be the same as the corresponding author listed in the authors section but isn’t required to be. In cases where the individuals are different, the corresponding author would be the appropriate person to contact for scientific issues whereas the point of contact would be the appropriate person to contact about technical issues with the AOP-KB entry itself. Corresponding authors and the point of contact are encouraged to monitor comments on their AOPs and develop or coordinate responses as appropriate. More help

Yutaka Kimura (email point of contact)

Contributors

List user names of all authors contributing to or revising pages in the AOP-KB that are linked to the AOP description. This information is mainly used to control write access to the AOP page and is controlled by the Point of Contact. More help

Yutaka Kimura

Status

The status section is used to provide AOP-KB users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. “Author Status” is an author defined field that is designated by selecting one of several options from a drop-down menu (Table 3). The “Author Status” field should be changed by the point of contact, as appropriate, as AOP development proceeds. See page 22 of the User Handbook for definitions of selection options. More help

Author status	OECD status	OECD project	SAAOP status
Open for citation & comment	EAGMST Under Review	1.48	Included in OECD Work Plan

This AOP was last modified on December 21, 2020 21:47

The date the AOP was last modified is automatically tracked by the AOP-KB. The date modified field can be used to evaluate how actively the page is under development and how recently the version within the AOP-Wiki has been updated compared to any snapshots that were generated. More help

Revision dates for related pages

Page	Revision Date/Time
Impaired IL-1R1 signaling	December 21, 2020 21:49
Suppression of T cell activation	November 18, 2019 01:08
Inhibition, Nuclear factor kappa B (NF-kB)	March 12, 2020 22:10
Increase, Increased susceptibility to infection	March 12, 2020 22:32
Impaired IL-1R1 signaling leads to Inhibition, Nuclear factor kappa B (NF-kB)	November 23, 2020 04:15
Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation	March 13, 2020 03:08
Suppression of T cell activation leads to Increase, Increased susceptibility to infection	March 13, 2020 03:21
IL-1 receptor antagonist（IL-1Ra）(Anakinra)	June 01, 2019 00:37
anti-IL-1b antibody (Canakinumab)	June 01, 2019 00:38
soluble IL-1R (Rilonacept)	June 01, 2019 00:38
anti-IL-1b antibody (Gevokizumab)	December 15, 2019 20:41
Dexamethasone	June 01, 2019 00:56
minocycline	June 01, 2019 00:32
Belnacasan (VX-765)	December 21, 2020 19:49
Pralnacasan (VX-740, HMR3480)	December 21, 2020 19:57
cinnamic aldehyde	June 01, 2019 00:37

Abstract

In the abstract section, authors should provide a concise and informative summation of the AOP under development that can stand-alone from the AOP page. Abstracts should typically be 200-400 words in length (similar to an abstract for a journal article). Suggested content for the abstract includes the following: The background/purpose for initiation of the AOP’s development (if there was a specific intent) A brief description of the MIE, AO, and/or major KEs that define the pathway A short summation of the overall WoE supporting the AOP and identification of major knowledge gaps (if any) If a brief statement about how the AOP may be applied (optional). The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance More help

The pleiotropic cytokine IL-1 mediates its biological functions via association with the signaling receptor IL-1R1. These may include initiation of innate immunity as well as acquired immunity, which are essential for assistance of host defense against infection. The trimeric complex consists of IL-1, IL-1R1 and IL-1R3 (a coreceptor, formerly IL-1R accessory protein) allows for the approximation of the Toll-IL-1-Receptor (TIR) domains of each receptor chain. MyD88 then binds to the TIR domains. The binding of MyD88 triggers a cascade of kinases that produce a strong pro-inflammatory signal leading to activation of NF-κB. The activation of NF-κB plays a principal role in the immunological function of IL-1. Namely, it stimulates innate immunity such as activation of dendritic cells and macrophages. It also stimulates T cells via activated dendritic function or directly. The activation of T cells is crucial for B cell proliferation and their antibody production. The cooperation by T cells and B cells constitutes a main part of host defense against infection. Therefore, the impaired IL-1R1 signaling either by the decreased IL-1 production or the inhibition of IL-1β binding to IL-1R1 by IL-1 receptor antagonist（IL-1Ra）or anti-IL-1β antibody) results in the blockade of the effects of the pleiotropic cytokine IL-1β leading to increased susceptibility to infection.

In this AOP, we selected the impaired IL-1R signaling as a molecular initiating event (MIE), and suppression of NF-κB, suppression of T cell activation, and increased susceptibility to infection as key events (KE).

Background (optional)

This optional subsection should be used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development. The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. Examples of potential uses of the optional background section are listed on pages 24-25 of the User Handbook. More help

The pleiotropic cytokine IL-1 mediates its biological functions via association with the signaling receptor IL-1R1. These may include initiation of innate immunity and assistance of host defense against infection, and sometimes, mediation of autoinflammatory, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever. The trimeric complex consists of IL-1, IL-1R1 and IL-1R3 (a coreceptor, formerly IL-1R accessory protein) allows for the approximation of the Toll-IL-1-Receptor (TIR) domains of each receptor chain. MyD88 then binds to the TIR domains. The binding of MyD88 triggers a cascade of kinases that produce a strong pro-inflammatory signal leading to activation of NF-κB and fundamental inflammatory responses such as the induction of cyclooxygenase type 2, production of multiple cytokines and chemokines, increased expression of adhesion molecules, or synthesis of nitric oxide. (Dinarello, 2018; Weber et al., 2010a, b).

Molecules like nuclear or mitochondrial DNA, adenosine triphosphate (ATP), uridine triphosphate (UTP), uric acid and high mobility group box 1 (HMGB1) are classified as damage associated molecular patterns (DAMPs). DAMPs are secreted or produced upon cellular injury or death and induce sterile inflammation. On the other hand, bacterial products like lipopolysaccharide (LPS), peptidoglycans, lipoprotein flagellins, bacterial RNA and DNA are some of the well-characterized pathogen associated molecular patterns (PAMPs). These DAMPs and PAMPs with a few exceptions bind to pattern recognition receptors (PRRs) such as toll-like receptor (TLRs) and nucleotide oligomerization domain (NOD) like receptors (NLRs). Proinflammatory mediators such as DAMPs, PAMPs, and various inflammatory cytokines or mediators including IL-1β itself activate innate immune mechanisms in the host leading to IL-1b production (Handa et al., 2016; Newton and Dixit, 2012; Yang et al., 2017). Besides transcriptional regulation and posttranscriptional level by RNA-binding proteins, pro-IL-1b protein requires proteolytic cleavage by active caspase-1 as the effector component of stimulation-induced multi-protein inflammasomes to acquire functional activity. Altogether, these different layers of regulation allow to fine tune IL-1b production under different pathophysiological conditions (Bent et al., 2018).

Therefore, the inhibition of various targets in different layers from the stimulation of PRPs or the receptors of proinflammatory cytokines, e.g., IL-1, IL-18, or TNFa, to the activation of NF-κB or the inhibition of posttranscriptional regulation of pro-IL-1b cause impaired IL-1R1 signaling. In addition, since IL-1 also mediates autoinflammatory syndromes, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever, several inhibitors against IL-1R1 have been developed. They are IL-1 receptor antagonist（IL-1Ra）, anakinumab (anti-IL-1β 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; Fleischmann et al., 2003; Genovese et al., 2004; Imagawa et al., 2013; Kullenberg et al., 2016; Lachmann et al., 2009; Lequerre et al., 2008; Migkos et al., 2015; Schlesinger et al., 2012; Yokota et al., 2017). In addition to these human data, the experiments using knockout mice revealed that the lack of IL-1 signaling led to bacterial, tuberculosis or viral infection(Guler et al., 2011; Horino et al., 2009; Juffermans et al., 2000; Tian et al., 2017; Yamada et al., 2000).

In addition to these human data, the experiments using knockout mice revealed that the lack of IL-1 signaling led to bacterial, tuberculosis or viral infection. (Guler et al., 2011; Horino et al., 2009; Juffermans et al., 2000; Tian et al., 2017; Yamada et al., 2000).

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)

An MIE is a specialised KE that represents the beginning (point of interaction between a stressor and the biological system) of an AOP. More help

Key Events (KE)

This table summarises all of the KEs of the AOP. This table is populated in the AOP-Wiki as KEs are added to the AOP. Each table entry acts as a link to the individual KE description page. More help

Adverse Outcomes (AO)

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Sequence	Type	Event ID	Title	Short name

MIE

1700

Impaired IL-1R1 signaling

2	KE	202	Inhibition, Nuclear factor kappa B (NF-kB)	Inhibition, Nuclear factor kappa B (NF-kB)
3	KE	1702	Suppression of T cell activation	Suppression of T cell activation

986

Increase, Increased susceptibility to infection

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarises all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP. Each table entry acts as a link to the individual KER description page.To add a key event relationship click on either Add relationship: events adjacent in sequence or Add relationship: events non-adjacent in sequence.For example, if the intended sequence of KEs for the AOP is [KE1 > KE2 > KE3 > KE4]; relationships between KE1 and KE2; KE2 and KE3; and KE3 and KE4 would be defined using the add relationship: events adjacent in sequence button. Relationships between KE1 and KE3; KE2 and KE4; or KE1 and KE4, for example, should be created using the add relationship: events non-adjacent button. This helps to both organize the table with regard to which KERs define the main sequence of KEs and those that provide additional supporting evidence and aids computational analysis of AOP networks, where non-adjacent KERs can result in artifacts (see Villeneuve et al. 2018; DOI: 10.1002/etc.4124).After clicking either option, the user will be brought to a new page entitled ‘Add Relationship to AOP.’ To create a new relationship, select an upstream event and a downstream event from the drop down menus. The KER will automatically be designated as either adjacent or non-adjacent depending on the button selected. The fields “Evidence” and “Quantitative understanding” can be selected from the drop-down options at the time of creation of the relationship, or can be added later. See the Users Handbook, page 52 (Assess Evidence Supporting All KERs for guiding questions, etc.). Click ‘Create [adjacent/non-adjacent] relationship.’ The new relationship should be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. To edit a key event relationship, click ‘Edit’ next to the name of the relationship you wish to edit. The user will be directed to an Editing Relationship page where they can edit the Evidence, and Quantitative Understanding fields using the drop down menus. Once finished editing, click ‘Update [adjacent/non-adjacent] relationship’ to update these fields and return to the AOP page.To remove a key event relationship to an AOP page, under Summary of the AOP, next to “Relationships Between Two Key Events (Including MIEs and AOs)” click ‘Remove’ The relationship should no longer be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. More help

Title	Adjacency	Evidence	Quantitative Understanding

Impaired IL-1R1 signaling leads to Inhibition, Nuclear factor kappa B (NF-kB)	adjacent	High	Moderate
Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation	adjacent	High	Moderate
Suppression of T cell activation leads to Increase, Increased susceptibility to infection	adjacent	High	Not Specified

Network View

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help

Stressors

Name	Evidence Term
IL-1 receptor antagonist（IL-1Ra）(Anakinra)	High
anti-IL-1b antibody (Canakinumab)	High
soluble IL-1R (Rilonacept)	High
anti-IL-1b antibody (Gevokizumab)	High
Dexamethasone	High
minocycline	High
Belnacasan (VX-765)	High
Pralnacasan (VX-740, HMR3480)	High
cinnamic aldehyde	High

Life Stage Applicability

Identify the life stage for which the KE is known to be applicable. More help

Life stage	Evidence
Not Otherwise Specified	High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. 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

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help

Sex	Evidence
Mixed	High

Overall Assessment of the AOP

This section addresses the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and WoE for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). The goal of the overall assessment is to provide a high level synthesis and overview of the relative confidence in the AOP and where the significant gaps or weaknesses are (if they exist). Users or readers can drill down into the finer details captured in the KE and KER descriptions, and/or associated summary tables, as appropriate to their needs.Assessment of the AOP is organised into a number of steps. Guidance on pages 59-62 of the User Handbook is available to facilitate assignment of categories of high, moderate, or low confidence for each consideration. While it is not necessary to repeat lengthy text that appears elsewhere in the AOP description (or related KE and KER descriptions), a brief explanation or rationale for the selection of high, moderate, or low confidence should be made. More help

Domain of Applicability

The relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Biological domain of applicability is informed by the “Description” and “Biological Domain of Applicability” sections of each KE and KER description (see sections 2G and 3E for details). In essence the taxa/life-stage/sex applicability is defined based on the groups of organisms for which the measurements represented by the KEs can feasibly be measured and the functional and regulatory relationships represented by the KERs are operative.The relevant biological domain of applicability of the AOP as a whole will nearly always be defined based on the most narrowly restricted of its KEs and KERs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the biological domain of applicability of the AOP as a whole would be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE and KER descriptions, the rationale for defining the relevant biological domain of applicability of the overall AOP should be briefly summarised on the AOP page. 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).

The NFKB1 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, and frog.

275 organisms have orthologs with human gene NFKB1.

(https://www.ncbi.nlm.nih.gov/gene/4790)

The RELB gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and frog.

216 organisms have orthologs with human gene RELB.

(https://www.ncbi.nlm.nih.gov/gene/5971)

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

Essentiality of the Key Events

An important aspect of assessing an AOP is evaluating the essentiality of its KEs. The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence.The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs.When assembling the support for essentiality of the KEs, authors should organise relevant data in a tabular format. The objective is to summarise briefly the nature and numbers of investigations in which the essentiality of KEs has been experimentally explored either directly or indirectly. See pages 50-51 in the User Handbook for further definitions and clarifications. More help

The experiments using knockout mice revealed that the deficiency of IL-1 signaling led to bacterial, tuberculosis or viral infection (Guler et al., 2011; Horino et al., 2009; Juffermans et al., 2000; Tian et al., 2017; Yamada et al., 2000).

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). Two IL-1 signaling antagonists, canakinumab (anti-IL-1b antibody) and rilonacept (soluble IL-1R) had been reported to increase susceptibility to infection (De Benedetti et al., 2018; Imagawa et al., 2013; Lachmann et al., 2009; Schlesinger et al., 2012).

In a similar way, defect of MyD88 signaling caused by knockout of mice gene or deficiency in human patient leads to the increased susceptibility to bacterial or tuberculosis infection (Fremond et al., 2004; Picard et al., 2010; Scanga et al., 2004; von Bernuth et al., 2008). Although MyD88 is also known to be involved in TLR signaling pathway, several reports suggested that MyD88-dependent response was IL-1 receptor-mediated but not TLR-mediated. These data suggest to essentiality of IL-1-MyD88 signaling pathway in host defense against infection.

Mice lacking NF-kB p50 are unable effectively to clear L. monocytogenes and are more susceptible to infection with S. peumoniae (Sha et al., 1995).

Evidence Assessment

The biological plausibility, empirical support, and quantitative understanding from each KER in an AOP are assessed together. Biological plausibility of each of the KERs in the AOP is the most influential consideration in assessing WoE or degree of confidence in an overall hypothesised AOP for potential regulatory application (Meek et al., 2014; 2014a). Empirical support entails consideration of experimental data in terms of the associations between KEs – namely dose-response concordance and temporal relationships between and across multiple KEs. It is examined most often in studies of dose-response/incidence and temporal relationships for stressors that impact the pathway. While less influential than biological plausibility of the KERs and essentiality of the KEs, empirical support can increase confidence in the relationships included in an AOP. For clarification on how to rate the given empirical support for a KER, as well as examples, see pages 53- 55 of the User Handbook. More help

The recent review of IL-1 pathway by Weber et al. has clearly described the intracellular signaling event from the binding of IL-1a or IL-1b to IL-1R to the activation of NF-kB through the assemble of MyD88 to the trimelic complex composed of IL-1, IL-R1, and IL-1RacP. The sequentiality and essentiality of each signaling molecule have been demonstrated by mice lacking relevant molecules (Weber et al., 2010a, b).

There were several reports that described that administration of IL-1R antagonist or neutralizing antibody led to the suppression of downstream phenomena, which included internalization of IL-1 (Dripps et al., 1991), production of PGE₂ (Hannum et al., 1990; Seckinger et al., 1990b), IL-6 (Goh et al., 2014), and T cell proliferation (Seckinger et al., 1990a).

Biological plausibility

Inhibition of IL-1 binding to IL-1 receptor leads to Inhibition, Nuclear factor kappa B (NF-kB)

IL-1α and IL-1β independently bind the type I IL-1 receptor (IL-1R1), which is ubiquitously expressed. The IL-1R3 (formerly IL-1R accessory protein (IL-1RAcP)) serves as a co-receptor that is required for signal transduction of IL-1/IL-1RI complexes.

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-1R3. 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. This is paralleled by the (auto)phosphorylation of IRAK4, which subsequently phosphorylates IRAK1 and IRAK2, and then this is followed by the recruitment and oligomerization of tumor necrosis factor–associated factor (TRAF) 6. Activation of NF-κB by IL-1 requires the activation of inhibitor of nuclear factor B (IκB) kinase 2 (IKK2). Activated IKK phosphorylates IκBα, which promotes its K48-linked polyubiquitination and subsequent degradation by the proteasome. IκB destruction allows the release of p50 and p65 NF-κB subunits and their nuclear translocation, which is the central step in activation of NF-κB. Both NF-κBs bind to a conserved DNA motif that is found in numerous IL-1–responsive genes. (Weber et al., 2010a, b)

Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation

In T lineage cells, the temporal regulation of NF-kb controls the stepwise differentiation and antigen-dependent selection of conventional and specialized subsets of T cells in response to T cell receptor and costimulatory, cytokines and growth factor signals. Cytokines include cytokines produced from macrophage or monocyte such as IL-1b. (Gerondakis et al., 2014)

Suppression of T cell activation leads to Increase, Increased susceptibility to infection

First type immunity drives resistance to viruses and intracellular bacteria, such as Listeria monocytogenes, Salmonella spp. and Mycobacteria spp., as well as to intracellular protozoan parasites such as Leishmania spp. The T helper 1 signature cytokine interferon-γ has a central role in triggering cytotoxic mechanisms including macrophage polarization towards an antimicrobial response associated with the production of high levels of reactive oxygen species and reactive nitrogen species, activation of CD8 cytotoxic T lymphocytes and natural killer cells to kill infected cells via the perforin and/or granzyme B-dependent lytic pathway or via the ligation of surface death receptors; and B cell activation towards the production of cytolytic antibodies that target infected cells for complement and Fc receptor-mediated cellular cytotoxicity.

Resistance to extracellular metazoan parasites and other large parasites is mediated and/or involves second type immunity. Pathogen neutralization is achieved via different mechanisms controlled by T 2 signature cytokines, including interleukin-4, IL-5 and IL-13, and by additional type 2 cytokines such as thymic stromal lymphopoietin, IL-25 or IL-33, secreted by damaged cell. T 2 signature cytokines drive B cell activation towards the production of high-affinity pathogen-specific IgG1 and IgE antibodies that function via Fc-dependent mechanisms to trigger the activation of eosinophils, mast cells and basophils, expelling pathogens across epithelia.

T17 immunity confers resistance to extracellular bacteria such as Klebsiella pneumoniae, Escherichia coli, Citrobacter rodentium, Bordetella pertussis, Porphyromonas gingivalis and Streptococcus pneumoniae, and also to fungi such as Candida albicans, Coccidioides posadasii, Histoplasma capsulatum and Blastomyces dermatitidis. Activation of T 17 cells by cognate T cell receptor (TCR–MHC class II interactions and activation of group 3 innate lymphoid cells (ILC3s) via engagement of IL-1 receptor (IL-1R) by IL-1β secreted from damaged cells lead to the recruitment and activation of neutrophils. T 17 immunopathology is driven to a large extent by products of neutrophil activation, such as ROS and elastase (reviewed by Soares et al. (Soares et al., 2017).

Based on these evidences, the insufficient T cell or B cell function causes impaired resistance to infection.

Empirical support

This table summarizes the empirical support obtained from the experiment using several inhibitor or gene targeting mice.

concordance table empirical data
Reference	Chmical Initiator or deleted gene	dose	Species	MIE	KE1	KE2	AO
Reference	Chmical Initiator or deleted gene	dose	Species	Inhibition of IL-1 binding to IL-1 receptor	Inhibition, Nuclear factor kappa B (NF-kB)	Suppression of T cell activation	Increase, Increased susceptibility to infection
Dripps et al. 1991	IL-1Ra (anakinra)			Equilibrium binding and kinetic experiments show that IL-1ra binds to the 80-kDa IL-1 receptor on the murine thymomcae ll line EL4 with an affinity (K_D = 150 pM) approximately equal to that of IL-la and IL-1b for this receptor
Sigma-Aldrich Specification Sheet	IL-1Ra (anakinra)			Determined by its ability to inhibit the IL-1alpha stimulation of murine D10S cell. The expected ED50 is 20-40 ng/ml in the presence of 50 pg/ml of IL-1alpha.
Fleischmann et al. 2003	IL-1Ra (anakinra)	100 mg of anakinra or placebo, administered daily by subcutaneous injection	human				Serious infectious episodes were observed more frequently in the anakinra group (2.1% versus 0.4% in the placebo group).
Genovese et al. 2004	IL-1Ra (anakinra)	treated with subcutaneous etanercept only (25 mg twice weekly), full-dosage etanercept (25 mg twice weekly) plus anakinra (100 mg/day), or half-dosage etanercept (25 mg once weekly) plus anakinra (100 mg/day) for 6 months	human				The incidence of serious infections (0% for etanercept alone, 3.7-7.4% for combination therapy), injection-site reactions, and neutropenia was increased with combination therapy.
Kullenberg et al. 2016	IL-1Ra (anakinra)	administered as daily s.c. injections	human				In total, 14 patients experienced 24 serious AEs (SAEs), all of which resolved during the study period. The most common types of SAEs were infections such as pneumonia and gastroenteritis.
Lequerre et al. 2008	IL-1Ra (anakinra)	treated with anakinra (1–2 mg/kg/day in children, 100 mg/day in adults)	human				Two patients stopped anakinra due to severe skin reaction, and two patients due to infection: one visceral leishmaniasis and one varicella.
Migkos et al. 2015	IL-1Ra (anakinra)		human				a case of tuberculous pyomyositis in a 85-year-old Caucasian patient with rheumatoid arthritis (RA) treated with steroids and anakinra.
Settas et al. 2007	IL-1Ra (anakinra)		human				reactivation of previous pulmonary tuberculosis (TBC) after 23 months of treatment with the IL-1 receptor antagonist anakinra.
Lee et al. 2004	IL-1Ra (anakinra)		intrathecal administration of IL-1ra (6 mg)		intrathecal pretreatment with IL-1ra (6 mg) or YVAD (0.5 mg) significantly inhibited NF-kB DNA-binding activity upregulation bilaterally (Fig. 3C). The intrathecal administration of IL-1ra or YVAD into non-inflamed animals produced no significant change in the DNA-binding activity of NF-kB p65.
Vallejo et al. 2014	IL-1Ra (anakinra)	In diabetic rats treated with anakinra (100 or 160 mg/Kg/day for 3 or 7 days before sacrifice)	rat		In diabetic rats treated with anakinra (100 or 160 mg/Kg/day for 3 or 7 days before sacrifice) a partial improvement of diabetic endothelial dysfunction occurred, together with a reduction of vascular NADPH oxidase and NF-κB activation.
Dhimolea et al. 2010	canakinumab			Canakinumab binds to human IL-1β with high affinity; the antibody-antigen dissociation equilibrium constant is approximately 35–40 pM. Cmax was 1.2, 1.2 and 1.5 pM for 1, 3 and 10 mg/kg antibody respectively, at days 42–56 after the first infusion.
De Benedetti et al. 2018	canakinumab	150 mg subcutaneously every 4 weeks	human				infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean fever, those with mevalonate kinase deficiency, and those with TRAPS, respectively), with a few being serious infections (6.6, 13.7, and 0.0 per 100 patient-years).
Imagawa et al. 2013	canakinumab	either 150 mg s.c. or 2 mg/kg for patients with a body weight ≤ 40 kg every 8 weeks for 24 weeks	human				Two patients had serious adverse events, which resolved with standard treatment.
Lachmann et al. 2009	canakinumab	received 150 mg of canakinumab subcutaneously every 8 weeks for up to 24 weeks	human				the incidence of suspected infections was greater in the canakinumab group than in the placebo group (P = 0.03). Two serious adverse events occurred during treatment with canakinumab: one case of urosepsis and an episode of vertigo.
Schlesinger et al. 2012	canakinumab	one dose of canakinumab 150 mg	human				Over the 24-week period, adverse events were reported in 66.2% (canakinumab) and 52.8% (TA) and serious adverse events were reported in 8.0% (canakinumab) and 3.5% (TA) of patients. Adverse events reported more frequently with canakinumab included infections, low neutrophil count and low platelet count.
Textbook of Pediatric Rheumatology (Sixth Edition), 2011	rilonacept		human	Rilonacept has a very high binding affinity for IL-1 (dissociation constant ~1 pM), and it is specific for IL-1β and IL-1α.
Hoffman et al. 2008	rilonacept	weekly subcutaneous injections (160 mg)	human				The incidence of patients reporting any type of infection was higher during study 1 in patients treated with rilonacept as compared with patients treated with placebo (48% versus 17%), with upper respiratory tract infections being the most frequently reported infection
Roell et al. 2010	gevokizumab (XOMA 052)		human		XOMA 052 neutralizes IL-1b stimulation of NFkB activation in HeLa cells stably expressing an NFkB-luciferase reporter construct with an IC₅₀ of ~1 pM at the EC₅₀ for this assay (25 pg/ml IL-1b).
Mansouri et al. 2015	gevokizumab (XOMA 052)	receive gevokizumab 60 mg subcutaneously every 4 weeks for a total of three injections (12 weeks) with a 4-week follow-up period	human				There were no significant adverse events related to the study medication, although one patient developed an abscess in a haematoma secondary to an injury.
Issafras et al. 2014	gevokizumab (XOMA 052)		human (HeLa cells stably transfected with a nuclear factor-kB (NF-kB) luciferase reporter plasmid)		an average K_B value (mean±S.D., n=3) of 4.8±4.4 pM
Palombella et al. 1994	MG-132		human (in vitro)		Both MG115 and MG132 (at 20-40 mM) markedly inhibited the formation of p50 in HeLa S100 extracts (Figure 4A, lanes 8-13).
Hellerbrand et al. 1998	MG-132		rat (in vitro)		ALLN (Fig. 3A) and MG132 (Fig. 3B) (10 mg/mL = 21mM) reduced the cytokine-mediated NFkB activation.
Arlt et al. 2001	MG-132		human (in vitro)		In all cell lines, gliotoxin, MG132 (10 mM) or sulfasalazine strongly reduced VP16-induced NF-kB-driven luciferase expression.
Ortiz-Lazareno et al. 2008	MG-132		human (in vitro)		The increase in NF-kB activation induced by LPS+PMA diminished significantly from 3.27-fold to 0.94-fold in the group treated with MG132(10 mM) and later stimulated with LPS+PMA (P < 0.002). The activation of NF-kB induced by LPS+PMA was blocked by MG132.
Yu and Malek 2001	MG-132		mice (in vitro)			MG132 (50mM) stabilized IL-2-induced activation of phosphorylated STAT5, which was especially evident after 2 h in culture (Fig. 5A, lane 7 versus 8).
Wang et al. 2011	MG-132		human (in vitro)			CMV-specific cytotoxicity of CD8(+) T cells was decreased in the presence of MG132.
Ohkusu-Tsukada et al. 2018	MG-132	repeatedly i.p. injected 200 nmol of MG132 on days 0, 3, 5, 7, 9, 11, 13, 15, 17, and 19.	mice (in vivo)			In vivo MG132 administration to NC/Nga mice with DNFB-induced dermatitis reduced Th17 cells but maintained the level of Th1 cells, resulting in the alleviation of dermatitis lesions by decreasing both serum IgE hyperproduction and mast cell migration.
Satou et al. 2004	bortezomib		human (in vitro, in vivo)			potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro
Orciuolo et al. 2007	bortezomib	0.1 mM, 1 mM, 10 mM	human (in vitro)			the percentage of CD69/TNFa positive T-cell reduces with the increment of bortezomib concentration.
Matsumoto et al. 2005	dehydroxymethylepoxyquinomicin (DHMEQ)		human		The addition of DHMEQ (10 mg/mL) completely inhibited the activated NF-KB for at least 8 hours.
Nishioka et al. 2008	dehydroxymethylepoxyquinomicin (DHMEQ)		human (in vitro)		DHMEQ (1mg/mL) blocked PHA-induced nuclear translocation of NF-kB in Jurkat cells via inhibition of degradation of IkBa.	Exposure of PBMC to PHA greatly stimulated expression of IFN-g, IL-2 and TNF-a (Fig. 3a). Pre-incubation of these cells with DHMEQ (1 mg/ml, 3 hr) greatly reduced PHA-stimulated expression of these cytokine genes (Fig. 3a). Similarly, PHA increased expression of IL-2 and IFN-c in Jurkat cells and pre-incubation of these cells with DHMEQ (1 mg/ml) decreased these levels by approximately half (Fig. 3b).
Alessiani et al. 1991	FK 506		human			Five of eight deaths were due to infection (62.5%). Overall, 50% of patients developed infection of which 38% suffered severe ones.
Fung et al. 1991	FK 506		human			The incidence of serious infections, despite the potency of FK 506, has not appeared to be alarming. The incidence of serious infections was about 50% less than seen in a historical group of patients given CyA. Of note is that the incidence of cytomegalovirus infections did not appear to be increased when compared with patients on CyA.
Ekberg et al. 2007	cyclosporine		human			The most commonly reported serious adverse events were cytomegalovirus (CMV) viremia, urinary tract infection and lymphocele (Table 3). The number of patients with opportunistic infections (serious and non-serious) was also similar amongst the groups, and cytomegalovirus infection was the most common opportunistic infection (Table 3).

Guler et al. 2011	i) IL-1RI^-/- ii) Autologous Qb virus-like particle-based vaccines against IL-1a and IL-1b	ii) immunized s.c. three times before (at week: −5, −3 and −1) and once at week 10 post-infection	mice				i) drastically increases mortality not only to high-dose intranasal infection but also to natural low-dose aerosol infection with Mycobacterium tuberculosis. ii) Blocking of IL-1a resulted in increased susceptibility to chronic infection with Mycobacterium tuberculosis. Increased listerial growth following IL-1aneutralization.
Parnet et al. 2003	IL-1RI^-/-				Activation of NFkB in response to IL-1b was no longer apparent in IL-1RI knockout mice, confirming that this receptor is essential for the transduction of IL-1 signal in the pituitary,
Yamada et al. 2001	NF-kB p50^-/-	knockout mice	mice				NF-kB p50 knockout mice were infected with Mycobacterium tuberculosis by placing them in the exposure chamber of an airborneinfection apparatus. These mice developed multifocal necrotic pulmonary lesions or lobar pneumonia. Compared with the levels in wild-type mice, pulmonary inducible nitric oxide synthase, interleukin-2 (IL-2), gamma interferon, and tumor necrosis factor alpha mRNA levels were significantly low but expression of IL-10 and transforming growth factor b mRNAs were within the normal ranges. The pulmonary IL-6 mRNA expression level was higher. C57BL/6 WT mice survived the entire 12-week experimental period, but NF-kB KO mice began to succumb to the disease at 6 weeks after infection, and all mice had died by 10 weeksafter infection (Fig. 1).
Weih et al. 1995	RelB^-/-	knockout mice	mice			RelB-deficient animals also had an impaired cellular immunity, as observed in contact sensitivity experiments.
Lin et al. 2015	Secreted IL-1α expression		mice			Both the percent and number of CD69+ T cells, CD69+ CD8+ T cells, and CD69+ CD4+ T cells increased by the expression of secreted IL-1α in the spleen
Nambu et al. 2006	IL-1a^-/-, IL-1b^-/-, IL-1a/b^-/-	knockout mice	mice			IL-1b, but not IL-1a, is required for antigen-specific T cell activation and the induction of local inflammation in the delayed-type hypersensitivity responses

Quantitative Understanding

Some proof of concept examples to address the WoE considerations for AOPs quantitatively have recently been developed, based on the rank ordering of the relevant Bradford Hill considerations (i.e., biological plausibility, essentiality and empirical support) (Becker et al., 2017; Becker et al, 2015; Collier et al., 2016). Suggested quantitation of the various elements is expert derived, without collective consideration currently of appropriate reporting templates or formal expert engagement. Though not essential, developers may wish to assign comparative quantitative values to the extent of the supporting data based on the three critical Bradford Hill considerations for AOPs, as a basis to contribute to collective experience.Specific attention is also given to how precisely and accurately one can potentially predict an impact on KEdownstream based on some measurement of KEupstream. This is captured in the form of quantitative understanding calls for each KER. See pages 55-56 of the User Handbook for a review of quantitative understanding for KER's. More help

Considerations for Potential Applications of the AOP (optional)

At their discretion, the developer may include in this section discussion of the potential applications of an AOP to support regulatory decision-making. This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale.To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page or 'Update and continue' to continue editing AOP text sections. The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page. More help

The impaired IL-1 signaling can lead to decreased host resistance to various infections. Therefore, the test guideline to detect chemicals that decrease IL-1 signaling is required to support regulatory decision-making. This AOP can promote the understanding of the usefulness of the test guideline.

References

List the bibliographic references to original papers, books or other documents used to support the AOP. More help

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