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Yutaka Kimura (1) Setsuya Aiba (1)
(1) Depertment of Dermatology, Tohoku University Graduate School of Medicine
Corresponding author: Setsuya Aiba
Point of Contact
Yutaka Kimura (email point of contact)
- Yutaka Kimura
|Author status||OECD status||OECD project||SAAOP status|
|Under development: Not open for comment. Do not cite|
This AOP was last modified on March 14, 2019 02:57
|Increase, Increased susceptibility to infection||March 13, 2019 23:49|
|Blocking of IL-1R||March 15, 2019 03:54|
|Decreased IL-1 production||March 15, 2019 05:48|
|Impaired IL-1 signaling||March 17, 2019 03:50|
|Suppressed MyD88||March 17, 2019 04:42|
|Inhibition, Nuclear factor kappa B (NF-kB)||March 17, 2019 05:29|
|Blocking of IL-1R leads to Impaired IL-1 signaling||December 24, 2018 23:56|
|Decreased IL-1 production leads to Impaired IL-1 signaling||December 25, 2018 00:01|
|Impaired IL-1 signaling leads to Suppressed MyD88||March 14, 2019 00:02|
|Suppressed MyD88 leads to Inhibition, Nuclear factor kappa B (NF-kB)||March 12, 2019 20:38|
|Inhibition, Nuclear factor kappa B (NF-kB) leads to Increase, Increased susceptibility to infection||March 12, 2019 20:39|
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. (Dinaarello et al.)
IL-1 also mediates autoinflammatory, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever.Consequently, IL-1 family cytokines have sophisticated regulatory mechanisms to control their activities including proteolytic processing for their activation and the deployment of soluble receptors and receptor antagonists to limit their activities. 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. Fleischmann et al. 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, Leguerre et al. 2008, Kullenberg et al. 2016, Migkos et al. 2015). As IL-1 signaling antagonists, two drugs went up to the market, anakinumab (anti-IL-1b antibody) and rilonacept (soluble IL-1R). Several reports described that the administration of these drugs led to increased susceptibility to infection. (Lachmann et al. 2009, Schlesinger et al. 2012, Imagawa et al. 2013, Yokota et al. 2017, De Benedetti et al. 2018) Addition to these human data, the experiments using knockout mice revealed that the deficient of IL-1 signaling led to bacterial, tuberculosis or viral infection. (Yamada et al. 2000, Horino et al. 2009, Guler et al. 2011, Juffermans et al. 2000, Tian et a. 2017) Moreover, Patients with defects in MyD88 gene have an increased susceptibility to pyogenic bacterial infections (von Bernuth et al. 2008, Picard et al. 2010).The fact that MyD88 knockout mice showed fatal mycobacterium tuberculosis infection supports the significance of MyD88. (Fremond et al. 2004, Scanga et al. 2004)
These data suggest that IL-1 signaling via MyD88 is indispensable for the defense against microorganisms, and assessment of IL-1 signaling is a good tool for screening the chemical that influence to the host defense.
Summary of the AOP
Events: Molecular Initiating Events (MIE)
|Sequence||Type||Event ID||Title||Short name|
|MIE||1570||Blocking of IL-1R||Blocking of IL-1R|
|MIE||1571||Decreased IL-1 production||Decreased IL-1 production|
|MIE||1572||Impaired IL-1 signaling||Impaired IL-1 signaling|
|KE||1573||Suppressed MyD88||Suppressed MyD88|
|KE||202||Inhibition, Nuclear factor kappa B (NF-kB)||Inhibition, Nuclear factor kappa B (NF-kB)|
|AO||986||Increase, Increased susceptibility to infection||Increase, Increased susceptibility to infection|
Relationships Between Two Key Events
(Including MIEs and AOs)
|Blocking of IL-1R leads to Impaired IL-1 signaling||adjacent||High||High|
|Decreased IL-1 production leads to Impaired IL-1 signaling||adjacent||High||High|
|Impaired IL-1 signaling leads to Suppressed MyD88||adjacent||High||High|
|Suppressed MyD88 leads to Inhibition, Nuclear factor kappa B (NF-kB)||adjacent||High||High|
|Inhibition, Nuclear factor kappa B (NF-kB) leads to Increase, Increased susceptibility to infection||adjacent||High||High|
Life Stage Applicability
Overall Assessment of the AOP
Domain of Applicability
Although there were several reports regarding sex deference of IL-1 immuno function (Musabak et al. 2003, Klein et al. 2016) or MyD88 immuno function (Hannah et al. 2008, Klein et al. 2010, Klein et al. 2016), there was no report which mentioned about sex deference in deficient mouse of IL-1 signaling or of MyD88, infection as adverse effect of IL-1 blocking agent, or MyD88 deficient patients.
Furthermore, in concern of infections as adverse effect of anakinra, mean of patient age were 11.0 years old (Goldbach-Mansky et al. 2006) and 11.53 years old (Sibley et al. 2012).
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.
Essentiality of the Key Events
Defect of IL-1 signaling caused by knockout of mice gene or administration of IL-1 receptor antagonist or neutralizing antibodies to human leads to the increased susceptibility to infection. Moreover, polymorphism of IL-1b or IL-1Ra leads to the increased susceptibility to tuberculosis or fungal infection.
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. 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.
KER1:Blocking of IL-1R leads to Impaired IL-1 signaling.
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. 1990), IL-6 (Goh et al. 2014), T cell proliferation (Seckinger et al. 1990).
KER2: Decreased IL-1 production leads to Impaired IL-1 signaling.
Considerations for Potential Applications of the AOP (optional)
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