Aop: 277

AOP Title


Inhibition of IL-1 signaling

Short name:


IL-1 inhibition

Graphical Representation


Click to download graphical representation template




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 Do not cite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


Revision dates for related pages

Page Revision Date/Time
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



Background (optional)


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)


Key Events (KE)


Adverse Outcomes (AO)


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)


Title Adjacency Evidence Quantitative Understanding
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

Network View





Life Stage Applicability


Taxonomic Applicability


Sex 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.

Evidence Assessment


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 PGE(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.

Quantitative Understanding


Considerations for Potential Applications of the AOP (optional)




De Benedetti, F., M. Gattorno, J. Anton, E. Ben-Chetrit, J. Frenkel, H. M. Hoffman, I. Kone-Paut, H. J. Lachmann, S. Ozen, A. Simon, A. Zeft, I. Calvo Penades, M. Moutschen, P. Quartier, O. Kasapcopur, A. Shcherbina, M. Hofer, P. J. Hashkes, J. Van der Hilst, R. Hara, S. Bujan-Rivas, T. Constantin, A. Gul, A. Livneh, P. Brogan, M. Cattalini, L. Obici, K. Lheritier, A. Speziale and G. Junge (2018). "Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes." N Engl J Med378(20): 1908-1919.

Dinarello, C. A. (2018). "Overview of the IL-1 family in innate inflammation and acquired immunity." Immunol Rev281(1): 8-27.

Dripps, D. J., B. J. Brandhuber, R. C. Thompson and S. P. Eisenberg (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 Chem266(16): 10331-10336.

Fremond, C. M., V. Yeremeev, D. M. Nicolle, M. Jacobs, V. F. Quesniaux and B. Ryffel (2004). "Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88." J Clin Invest114(12): 1790-1799.

Genovese, M. C., S. Cohen, L. Moreland, D. Lium, S. Robbins, R. Newmark and P. Bekker (2004). "Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate." Arthritis Rheum50(5): 1412-1419.

Goh, A. X., S. Bertin-Maghit, S. Ping Yeo, A. W. Ho, H. Derks, A. Mortellaro and C. I. Wang (2014). "A novel human anti-interleukin-1beta neutralizing monoclonal antibody showing in vivo efficacy." MAbs6(3): 765-773.

Goldbach-Mansky, R., N. J. Dailey, S. W. Canna, A. Gelabert, J. Jones, B. I. Rubin, H. J. Kim, C. Brewer, C. Zalewski, E. Wiggs, S. Hill, M. L. Turner, B. I. Karp, I. Aksentijevich, F. Pucino, S. R. Penzak, M. H. Haverkamp, L. Stein, B. S. Adams, T. L. Moore, R. C. Fuhlbrigge, B. Shaham, J. N. Jarvis, K. O'Neil, R. K. Vehe, L. O. Beitz, G. Gardner, W. P. Hannan, R. W. Warren, W. Horn, J. L. Cole, S. M. Paul, P. N. Hawkins, T. H. Pham, C. Snyder, R. A. Wesley, S. C. Hoffmann, S. M. Holland, J. A. Butman and D. L. Kastner (2006). "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition." N Engl J Med355(6): 581-592.

Guler, R., S. P. Parihar, G. Spohn, P. Johansen, F. Brombacher and M. F. Bachmann (2011). "Blocking IL-1alpha but not IL-1beta increases susceptibility to chronic Mycobacterium tuberculosis infection in mice." Vaccine29(6): 1339-1346.

Hannah, M. F., V. B. Bajic and S. L. Klein (2008). "Sex differences in the recognition of and innate antiviral responses to Seoul virus in Norway rats." Brain Behav Immun22(4): 503-516.

Hannum, C. H., C. J. Wilcox, W. P. Arend, F. G. Joslin, D. J. Dripps, P. L. Heimdal, L. G. Armes, A. Sommer, S. P. Eisenberg and R. C. Thompson (1990). "Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor." Nature343(6256): 336-340.

Horino, T., T. Matsumoto, H. Ishikawa, S. Kimura, M. Uramatsu, M. Tanabe, K. Tateda, S. Miyazaki, Y. Aramaki, Y. Iwakura, M. Yoshida, S. Onodera and K. Yamaguchi (2009). "Interleukin-1 deficiency in combination with macrophage depletion increases susceptibility to Pseudomonas aeruginosa bacteremia." Microbiol Immunol53(9): 502-511.

Imagawa, T., R. Nishikomori, H. Takada, S. Takeshita, N. Patel, D. Kim, K. Lheritier, T. Heike, T. Hara and S. Yokota (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 Rheumatol31(2): 302-309.

Juffermans, N. P., S. Florquin, L. Camoglio, A. Verbon, A. H. Kolk, P. Speelman, S. J. van Deventer and T. van Der Poll (2000). "Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis." J Infect Dis182(3): 902-908.

Klein, S. L. and K. L. Flanagan (2016). "Sex differences in immune responses." Nat Rev Immunol16(10): 626-638.

Klein, S. L., A. Jedlicka and A. Pekosz (2010). "The Xs and Y of immune responses to viral vaccines." Lancet Infect Dis10(5): 338-349.

Kullenberg, T., M. Lofqvist, M. Leinonen, R. Goldbach-Mansky and H. Olivecrona (2016). "Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes." Rheumatology (Oxford)55(8): 1499-1506.

Lachmann, H. J., I. Kone-Paut, J. B. Kuemmerle-Deschner, K. S. Leslie, E. Hachulla, P. Quartier, X. Gitton, A. Widmer, N. Patel and P. N. Hawkins (2009). "Use of canakinumab in the cryopyrin-associated periodic syndrome." N Engl J Med360(23): 2416-2425.

Lequerre, T., P. Quartier, D. Rosellini, F. Alaoui, M. De Bandt, O. Mejjad, I. Kone-Paut, M. Michel, E. Dernis, M. Khellaf, N. Limal, C. Job-Deslandre, B. Fautrel, X. Le Loet and J. Sibilia (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 Dis67(3): 302-308.

Migkos, M. P., G. A. Somarakis, T. E. Markatseli, M. Matthaiou, P. Kosta, P. V. Voulgari and A. A. Drosos (2015). "Tuberculous pyomyositis in a rheumatoid arthritis patient treated with anakinra." Clin Exp Rheumatol33(5): 734-736.

Musabak, U., E. Bolu, M. Ozata, C. Oktenli, A. Sengul, A. Inal, Z. Yesilova, G. Kilciler, I. C. Ozdemir and I. H. Kocar (2003). "Gonadotropin treatment restores in vitro interleukin-1beta and tumour necrosis factor-alpha production by stimulated peripheral blood mononuclear cells from patients with idiopathic hypogonadotropic hypogonadism." Clin Exp Immunol132(2): 265-270.

Picard, C., H. von Bernuth, P. Ghandil, M. Chrabieh, O. Levy, P. D. Arkwright, D. McDonald, R. S. Geha, H. Takada, J. C. Krause, C. B. Creech, C. L. Ku, S. Ehl, L. Marodi, S. Al-Muhsen, S. Al-Hajjar, A. Al-Ghonaium, N. K. Day-Good, S. M. Holland, J. I. Gallin, H. Chapel, D. P. Speert, C. Rodriguez-Gallego, E. Colino, B. Z. Garty, C. Roifman, T. Hara, H. Yoshikawa, S. Nonoyama, J. Domachowske, A. C. Issekutz, M. Tang, J. Smart, S. E. Zitnik, C. Hoarau, D. S. Kumararatne, A. J. Thrasher, E. G. Davies, C. Bethune, N. Sirvent, D. de Ricaud, Y. Camcioglu, J. Vasconcelos, M. Guedes, A. B. Vitor, C. Rodrigo, F. Almazan, M. Mendez, J. I. Arostegui, L. Alsina, C. Fortuny, J. Reichenbach, J. W. Verbsky, X. Bossuyt, R. Doffinger, L. Abel, A. Puel and J. L. Casanova (2010). "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency." Medicine (Baltimore)89(6): 403-425.

Scanga, C. A., A. Bafica, C. G. Feng, A. W. Cheever, S. Hieny and A. Sher (2004). "MyD88-deficient mice display a profound loss in resistance to Mycobacterium tuberculosis associated with partially impaired Th1 cytokine and nitric oxide synthase 2 expression." Infect Immun72(4): 2400-2404.

Schlesinger, N., R. E. Alten, T. Bardin, H. R. Schumacher, M. Bloch, A. Gimona, G. Krammer, V. Murphy, D. Richard and A. K. So (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 Dis71(11): 1839-1848.

Seckinger, P., M. T. Kaufmann and J. M. Dayer (1990). "An interleukin 1 inhibitor affects both cell-associated interleukin 1-induced T cell proliferation and PGE2/collagenase production by human dermal fibroblasts and synovial cells." Immunobiology180(4-5): 316-327.

Sibley, C. H., N. Plass, J. Snow, E. A. Wiggs, C. C. Brewer, K. A. King, C. Zalewski, H. J. Kim, R. Bishop, S. Hill, S. M. Paul, P. Kicker, Z. Phillips, J. G. Dolan, B. Widemann, N. Jayaprakash, F. Pucino, D. L. Stone, D. Chapelle, C. Snyder, J. A. Butman, R. Wesley and R. Goldbach-Mansky (2012). "Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: a cohort study to determine three- and five-year outcomes." Arthritis Rheum64(7): 2375-2386.

Tian, T., M. Q. Jin and K. Dubin (2017). "IL-1R Type 1-Deficient Mice Demonstrate an Impaired Host Immune Response against Cutaneous Vaccinia Virus Infection."  198(11): 4341-4351.

von Bernuth, H., C. Picard, Z. Jin, R. Pankla, H. Xiao, C. L. Ku, M. Chrabieh, I. B. Mustapha, P. Ghandil, Y. Camcioglu, J. Vasconcelos, N. Sirvent, M. Guedes, A. B. Vitor, M. J. Herrero-Mata, J. I. Arostegui, C. Rodrigo, L. Alsina, E. Ruiz-Ortiz, M. Juan, C. Fortuny, J. Yague, J. Anton, M. Pascal, H. H. Chang, L. Janniere, Y. Rose, B. Z. Garty, H. Chapel, A. Issekutz, L. Marodi, C. Rodriguez-Gallego, J. Banchereau, L. Abel, X. Li, D. Chaussabel, A. Puel and J. L. Casanova (2008). "Pyogenic bacterial infections in humans with MyD88 deficiency." Science321(5889): 691-696.

Yamada, H., S. Mizumo, R. Horai, Y. Iwakura and I. Sugawara (2000). "Protective role of interleukin-1 in mycobacterial infection in IL-1 alpha/beta double-knockout mice." Lab Invest80(5): 759-767.

Yokota, S., T. Imagawa, R. Nishikomori, H. Takada, K. Abrams, K. Lheritier, T. Heike and T. Hara (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 Rheumatol35 Suppl 108(6): 19-26.