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Aop: 277

AOP Title

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Short name:

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IL-1 inhibition

Graphical Representation

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Authors

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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

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Yutaka Kimura   (email point of contact)

Contributors

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• Yutaka Kimura

Status

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This AOP was last modified on August 07, 2019 05:52

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Revision dates for related pages

Page	Revision Date/Time
Increase, Increased susceptibility to infection	June 25, 2019 21:43
Blocking of IL-1R	June 01, 2019 00:21
Decreased IL-1 production	June 24, 2019 03:16
Impaired IL-1 signaling	June 24, 2019 04:49
Inhibition, Nuclear factor kappa B (NF-kB)	June 25, 2019 21:32
Impaired T cell activation	June 25, 2019 21:37
Impaired Ab production	June 25, 2019 21:40
Decreased IL-1 production leads to Impaired IL-1 signaling	June 25, 2019 21:49
Blocking of IL-1R leads to Impaired IL-1 signaling	June 25, 2019 21:46
Impaired IL-1 signaling leads to Inhibition, Nuclear factor kappa B (NF-kB)	June 25, 2019 21:51
Inhibition, Nuclear factor kappa B (NF-kB) leads to Impaired T cell activation	June 25, 2019 21:53
Impaired T cell activation leads to Impaired Ab production	June 25, 2019 21:54
Impaired Ab production leads to Increase, Increased susceptibility to infection	June 25, 2019 21:55
minocycline	June 01, 2019 00:32
Pralnacasan (VX-740) and Belnacasan (VX-765)	June 01, 2019 00:36
cinnamic aldehyde	June 01, 2019 00:37
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
Dexamethasone	June 01, 2019 00:56

Abstract

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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 principle 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 cell 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. 

 

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 confirmed. In addition, the biological plausibilities that suppressed NF-kB activation leads to impaired T cell activation, resulting in impaired antibody production and that impaired T cell function and antibody production lead to increased susceptibility to infection is supported by quite a few published works.

 

IL-1 also mediates several autoinflammatory syndromes. Therefore, several inhibitors against IL-1 signaling such as IL-1Ra (generic anakinra) , canakinumab (anti-IL-1β antibody) and rilonacept (soluble IL-1R) have been developed. After these inhibitors became available to treat these disorders, it became clear that these inhibitors increased the frequency of serious bacterial infection. Similarly, the experiments using knockout mice revealed that the lack of IL-1 signaling led to bacterial infection, tuberculosis or viral infection. 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. Although the effects of dexamethasone are pleiotropic, it is well known to increase the susceptibility to bacterial, fungal, or viral infection. Minocycline or two caspase-1 inhibitors, Pralnacasan (VX-740) and Belnacasan(VX-765, also HMR3480 that are orally absorbed compounds and synthetized as prodrugs which are then converted into the active principle, VRT-018858 and VRT-043198, respectively 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. Recently, it has been reported that cinnamicaldehyde suppresses serum IL-1β level in endotoxin poisoning mice. These data suggest that chemicals as well as drugs can suppress IL-1 signaling through their inhibitory effects on IL-1β. Taken together, developing the AOP for inhibition of IL-1 signaling is mandatory.

Background (optional)

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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).

 

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, and pralnacasan (VX-740) and belnacasan(VX-765) that are orally absorbed compounds and synthetized as prodrugs which are then converted into the active principle, VRT-018858 and VRT-043198, respectively (Fenini et al., 2017)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., 2017). 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

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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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)

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Title	Adjacency	Evidence	Quantitative Understanding

Decreased IL-1 production leads to Impaired IL-1 signaling	adjacent	High	High
Blocking of IL-1R 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 Impaired Ab production	adjacent	High	High
Impaired Ab production leads to Increase, Increased susceptibility to infection	adjacent	High	High

Network View

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Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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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.

Essentiality of the Key Events

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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). 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).

Evidence Assessment

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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. 1990), IL-6 (Goh et al. 2014), and T cell proliferation (Seckinger et al. 1990).

Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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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

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Yokota, S., Imagawa, T., Nishikomori, R., Takada, H., Abrams, K., Lheritier, K., Heike, T., Hara, T., 2017. Long-term safety and efficacy of canakinumab in cryopyrin-associated periodic syndrome: results from an open-label, phase III pivotal study in Japanese patients. Clin Exp Rheumatol 35 Suppl 108, 19-26.