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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 Do not cite|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 May 23, 2019 03:05
|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|
|Inhibition, Nuclear factor kappa B (NF-kB)||March 17, 2019 05:29|
|Impaired T cell activation||December 24, 2018 23:24|
|Impaired Ab production||May 23, 2019 02:56|
|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 Inhibition, Nuclear factor kappa B (NF-kB)||May 23, 2019 02:54|
|Inhibition, Nuclear factor kappa B (NF-kB) leads to Impaired T cell activation||May 23, 2019 02:58|
|Impaired T cell activation leads to Increase, Increased susceptibility to infection||December 25, 2018 00:12|
|Impaired T cell activation leads to Impaired Ab production||May 23, 2019 03:00|
|Impaired Ab production leads to Increase, Increased susceptibility to infection||May 23, 2019 03:00|
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., 2010).
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. Therefore, several inhibitors against IL-1 signaling have been developed. IL-1 receptor antagonist（IL-1Ra）was purified in 1990, and the cDNA was 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 was 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. 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 also 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-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; Imagawa et al., 2013; Lachmann et al., 2009; 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).
Beside the blocking of IL-1 binding to its receptor, several drugs also suppress the production of IL-1. Dexamethasone is one of the representatives that significantly suppress IL-1β production from monocytes (Finch-Arietta and Cochran, 1991). Minocycline also suppress IL-1 signaling by the inhibition of caspase-1 activation, which is an essential enzyme for maturation of pro- IL-1β and the secretion of mature IL-1β(Vincent and Mohr, 2007). Recently, it has been reported that cinnamicaldehyde suppresses serum IL-1β level in endotoxin poisoning mice (Xu et al., 2016). These data suggest that chemicals as well as drugs can suppress IL-1 signaling through their inhibitory effects on IL-1β.
In this AOP, we considered 2 MIEs, such as blocking IL-1 R and decreased IL-1 production. Either MIE leads to reduced IL-1 signaling. The biological plausibility of the signaling cascade from the activation of IL-1R to the activation of NF-kB is already accepted. In addition, the biological plausibility that suppressed NF-kB activation leads to impaired T cell activation, resulting in impaired antibody production and impaired T cell and antibody production lead to increased susceptibility to infection is confirmed.
Moreover, Patients with defects in MyD88 gene have an increased susceptibility to pyogenic bacterial infections (Picard et al., 2010; von Bernuth et al., 2008)(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||202||Inhibition, Nuclear factor kappa B (NF-kB)||Inhibition, Nuclear factor kappa B (NF-kB)|
|KE||1569||Impaired T cell activation||Impaired T cell activation|
|KE||1644||Impaired Ab production||Impaired Ab production|
|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 Inhibition, Nuclear factor kappa B (NF-kB)||adjacent||High||High|
|Inhibition, Nuclear factor kappa B (NF-kB) leads to Impaired T cell activation||adjacent||High||High|
|Impaired T cell activation leads to Increase, Increased susceptibility to infection||adjacent||High||High|
|Impaired T cell activation leads to Impaired Ab production||adjacent||High||High|
|Impaired Ab production 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
The experiments using knockout mice revealed that the deficient 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). 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).
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.
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).
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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