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Aop: 277

AOP Title

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Inhibition of IL-1 binding to IL-1 receptor leading to increased susceptibility to infection

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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Author status OECD status OECD project SAAOP status
Open for citation & comment


This AOP was last modified on November 18, 2019 02:38

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Revision dates for related pages

Page Revision Date/Time
Inhibition of IL-1 binding to IL-1 receptor November 18, 2019 00:38
Suppression of T cell activation November 18, 2019 01:08
Inhibition, Nuclear factor kappa B (NF-kB) November 18, 2019 00:47
Increase, Increased susceptibility to infection November 18, 2019 22:54
Inhibition of IL-1 binding to IL-1 receptor leads to Inhibition, Nuclear factor kappa B (NF-kB) November 18, 2019 01:22
Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation November 18, 2019 07:00
Suppression of T cell activation leads to Increase, Increased susceptibility to infection November 18, 2019 02:06
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

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 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 the inhibition of IL-1 binding to IL-1 receptor as a MIE. The biological plausibility of the signaling cascade from IL-1 receptor activation to the activation of NF-kB is already confirmed. In addition, the biological plausibility that suppressed NF-kB activation leads to impaired T cell activation, resulting in impaired antibody production and increased susceptibility to infection is supported by quite a few published works.

 

IL-1 also mediates several autoinflammatory syndromes. Therefore, several inhibitors against IL-1R stimulation such as IL-1Ra (generic anakinra), canakinumab (anti-IL-1β antibody) and rilonacept (soluble IL-1R) have been developed. Indeed, after these inhibitors became available to treat these disorders, it became clear that these inhibitors increased the frequency of serious bacterial infection. Taken together, developing the AOP for “inhibition of IL-1 binding to IL-1 receptor leading to increased susceptibility to infection” 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. Therefore, several inhibitors against IL-1 signaling have been developed. Recombinant IL-1Ra (generic anakinra) is fully active in blocking the IL-1R1, and therefore, the activities of IL-1α and IL-1β. (Dripps et al., 1991) Anakinra was approved for the treatment of rheumatoid arthritis and cryopyrin-associated periodic syndrome (CAPS). Although anakinra is a safe drug in general, several papers reported that anakinra increased susceptibility to bacterial and tuberculosis infection (Genovese et al., 2004; Kullenberg et al., 2016; Lequerre et al., 2008; Migkos et al., 2015). Similarly, other IL-1 signaling antagonists, canakinumab (anti-IL-1β antibody) and rilonacept (soluble IL-1R) have been reported increase 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). 

              In this AOP, we considered inhibition of IL-1R activation, as a MIE. 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.       


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
1 MIE 1700 Inhibition of IL-1 binding to IL-1 receptor Inhibition of IL-1 binding to IL-1 receptor
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
4 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
Inhibition of IL-1 binding to IL-1 receptor leads to Inhibition, Nuclear factor kappa B (NF-kB) adjacent High High
Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation adjacent High High
Suppression of T cell activation 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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Life stage Evidence
Not Otherwise Specified High

Taxonomic Applicability

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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

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Sex Evidence
Mixed High

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).

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

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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) (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, there are several reports indicating that serious infectious episodes were observed more frequently in the anakinra group (Fleischmann et al., 2003)(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). 


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. The sequentiality and essentiality of each signaling molecule have been demonstrated by mice lacking relevant molecules (Weber et al., 2010a, b).


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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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.

Dinarello, C.A., 2018. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev 281, 8-27.

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.

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.

Guler, R., Parihar, S.P., Spohn, G., Johansen, P., Brombacher, F., Bachmann, M.F., 2011. Blocking IL-1alpha but not IL-1beta increases susceptibility to chronic Mycobacterium tuberculosis infection in mice. Vaccine 29, 1339-1346.

Horino, T., Matsumoto, T., Ishikawa, H., Kimura, S., Uramatsu, M., Tanabe, M., Tateda, K., Miyazaki, S., Aramaki, Y., Iwakura, Y., Yoshida, M., Onodera, S., Yamaguchi, K., 2009. Interleukin-1 deficiency in combination with macrophage depletion increases susceptibility to Pseudomonas aeruginosa bacteremia. Microbiol Immunol 53, 502-511.

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.

Juffermans, N.P., Florquin, S., Camoglio, L., Verbon, A., Kolk, A.H., Speelman, P., van Deventer, S.J., van Der Poll, T., 2000. Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis. J Infect Dis 182, 902-908.

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.

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.

Tian, T., Jin, M.Q., Dubin, K., 2017. IL-1R Type 1-Deficient Mice Demonstrate an Impaired Host Immune Response against Cutaneous Vaccinia Virus Infection.  198, 4341-4351.

Weber, A., Wasiliew, P., Kracht, M., 2010a. Interleukin-1 (IL-1) pathway. Sci Signal 3, cm1.

Weber, A., Wasiliew, P., Kracht, M., 2010b. Interleukin-1beta (IL-1beta) processing pathway. Sci Signal 3, cm2.

Yamada, H., Mizumo, S., Horai, R., Iwakura, Y., Sugawara, I., 2000. Protective role of interleukin-1 in mycobacterial infection in IL-1 alpha/beta double-knockout mice. Lab Invest 80, 759-767.

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.