Relationship: 2002



Inhibition of IL-1 binding to IL-1 receptor leads to Inhibition, Nuclear factor kappa B (NF-kB)

Upstream event


Inhibition of IL-1 binding to IL-1 receptor

Downstream event


Inhibition, Nuclear factor kappa B (NF-kB)

Key Event Relationship Overview


AOPs Referencing Relationship


AOP Name Adjacency Weight of Evidence Quantitative Understanding
Inhibition of IL-1 binding to IL-1 receptor leading to increased susceptibility to infection adjacent High Moderate

Taxonomic Applicability


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


Sex Evidence
Unspecific High

Life Stage Applicability


Term Evidence
All life stages High

Key Event Relationship Description


The initial step in IL-1 signal transduction is a ligand-induced conformational change in the first extracellular domain of the IL-1RI that facilitates recruitment of IL-1RacP. Through conserved cytosolic regions called Toll- and IL-1R–like (TIR) domains, the trimeric complex rapidly assembles two intracellular signaling proteins, myeloid differentiation primary response gene 88 (MYD88) and interleukin-1 receptor–activated protein kinase (IRAK) 4. IL-1, IL-1RI, IL-RAcP, MYD88, and IRAK4 form a stable IL-1–induced first signaling module. The binding of MyD88 triggers a cascade of kinases that produce a strong pro-inflammatory signal leading to activation of NF-κB. reviewed by Brikos et al. (Brikos et al., 2007) and Weber et al.  (Weber et al., 2010).

Therefore, the suppression of the binding of IL-1 to IL-1R1 suppresses activation of NF-κB.

Evidence Supporting this KER


Biological Plausibility


IL-1α and IL-1β independently bind the type I IL-1 receptor (IL-1R1), which is ubiquitously expressed. IL-1Ra binds IL-1R but does not initiate IL-1 signal transduction (Dripps et al., 1991). Recombinant IL-1Ra (anakinra) is fully active in blocking the IL-1R1, and therefore, the biological activities of IL-1α and IL-1β. The binding of IL-1α and IL-1β to IL-1R1 can be suppressed by soluble IL-R like rilonacept. The binding of IL-1β to IL-1R1 can also be inhibited by anti-IL-1β antibody (anti-IL-1β antibody). Therefore, the inhibition of IL-1 binding to IL-1R1 cannot activate NF-κB.

Empirical Evidence


IL-1Ra blocks IL-1 signaling:

IL-1Ra down-modulates EGF receptor (3 nM of ED50) by IL-1 stimulation (Dripps et al., 1991)

IL-1Ra suppresses IL-1-induced endothelial cell-leukocyte adhesion (approximately 10 ng/ml of ED50) (Dripps et al., 1991)

IL-1Ra suppresses rhIL-1a-induced mouse thymocytes proliferation (ED50 almost 3 mg/mL) (Arend et al., 1990)

IL-1Ra competed for binding of 125I-IL-1a to type I IL-1R present on EL4 thymoma cells, 3T3 fibroblasts, hepatocytes, and Chinese hamster ovary cells expressing recombinant mouse type I IL-1R. The IC50 values for IL-1ra binding (ranging from 2 to 4 ng/ml) were similar to those of IL-1a. (McIntyre et al., 1991)

Recombinant mIL-1Ra competitively inhibited 125I-labeled IL-1 alpha binding to murine type I IL-1R present on EL4 6.1 cells (Ki value of 0.21 nM) and antagonized IL-1-stimulated co-mitogenesis in murine thymocytes (0.7 x 10(6)-1.1 x 10(6) units/mg). (Shuck et al., 1991)

Peripheral blood mononuclear cells (PBMC) obtained after completion of the IL-lra infusion synthesized significantly less interleukin 6 ex vivo than PBMC from saline-injected controls. (Granowitz et al., 1992)

Canakinumab (ACZ885, Ilaris) blocks IL-1 signaling

Canakinumab binds to human IL-1β with high affinity; the antibody-antigen dissociation equilibrium constant is approximately 35–40 pM(Dhimolea, 2010).

The antibody binds to human IL-1β with high affinity (about 40 pmol/l). The antibody was found to neutralize the bioactivity of human IL-1β on primary human fibroblasts in vitro 44.6 pmol/l (7.1 ± 0.56 ng/ml; n = 6) of ED50. Application of Canakinumab intraperitoneally 2 hours before injecting the IL-1β producing cells completely suppressed joint swelling (0.06 mg/kg of EC50) (Alten et al., 2008).

Primary human fibroblasts are stimulated with recombinant IL-1b or conditioned medium obtained from LPS-stimulated human PBMCs in the presence of various concentrations of Cankinumab or IL-1RA ranging from 6 to 18,000 pM. Supernatant is taken after 16 h stimulation and assayed for IL-6 by ELISA. Canakinumab typically have 1 nM or less of EC50 for inhibition of IL-6 production (Canakinumab Patent Application WO02/16436.)

Rilonacept (IL-1 Trap, Arcalyst) blocks IL-1 signaling:

Incubation of the human MRC5 fibroblastic cell line with IL-1β induces secretion of IL-6. At a constant amount of IL-1β (4 pM), the IC50 of the IL-1 trap is ∼2 pM. Another unique property of the IL-1 trap is that it not only blocks IL-1β, but also blocks IL-1α with high affinity (KD = ∼3 pM; data not shown). The titration curve of IL-1 trap in the presence of 10 pM IL-1β shows an IC50 of 6.5 pM, which corresponds to a calculated KD of 1.5 pM (This affinity is 100 times higher than that of the soluble single component receptor IL-1RI (Economides et al., 2003).

Uncertainties and Inconsistencies


Quantitative Understanding of the Linkage


See Empirical Evidence.

Response-response Relationship


IL-1Ra blocks IL-1 signaling:

Suppression of IL-1-induced IL-1, TNFa, or IL-6 synthesis was dose-dependent (P ≦ .0001). At a twofold molar excess, IL-lra inhibited IL-1-induced IL-1 or TNFa synthesis by 50% (P < .01); an equimolar concentration of IL-lra inhibited synthesis of these two cytokines by over 20% (P < .05). A 10-fold molar excess of IL-lra over IL-lb reduced IL-lb-induced IL-la by 95% (P = .01) and IL-la-induced IL-1b by 73% (P < .01). In elutriated monocytes, a 10-fold molar excess of IL-lra reduced IL-lb-induced IL-la by 82% (P < .05), TNFa by 64% (P = .05), and IL-6 by 47% (P < .05). (Granowitz et al., 1992)

Rilonacept (IL-1 Trap, Arcalyst) blocks IL-1 signaling:

The titration curve of IL-1 trap in the presence of 10 pM IL-1β shows an IC50 of 6.5 pM, which corresponds to a calculated KD of 1.5 pM (This affinity is 100 times higher than that of the soluble single component receptor IL-1RI (Economides et al., 2003).



Known modulating factors


Known Feedforward/Feedback loops influencing this KER


Domain of Applicability




Alten, R., Gram, H., Joosten, L.A., et al., 2008. The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis. Arthritis Res Ther 10, R67.

Arend, W.P., Welgus, H.G., Thompson, R.C., et al., 1990. Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest 85, 1694-1697.

Brikos, C., Wait, R., Begum, S., et al., 2007. Mass spectrometric analysis of the endogenous type I interleukin-1 (IL-1) receptor signaling complex formed after IL-1 binding identifies IL-1RAcP, MyD88, and IRAK-4 as the stable components. Mol Cell Proteomics 6, 1551-1559.

De Benedetti, F., Gattorno, M., Anton, J., et al., 2018. Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. N Engl J Med 378, 1908-1919.

Dhimolea, E., 2010. Canakinumab. MAbs 2, 3-13.

Dripps, D.J., Brandhuber, B.J., Thompson, R.C., et al., 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.

Economides, A.N., Carpenter, L.R., Rudge, J.S., et al., 2003. Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat Med 9, 47-52.

Fleischmann, R.M., Schechtman, J., Bennett, R., et al., 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., et al., 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.

Granowitz, E.V., Clark, B.D., Vannier, E., et al., 1992. Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: I. IL-1 receptor antagonist inhibits IL-1-induced cytokine synthesis and blocks the binding of IL-1 to its type II receptor on human monocytes. Blood 79, 2356-2363.

Imagawa, T., Nishikomori, R., Takada, H., et al., 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.

Kullenberg, T., Lofqvist, M., Leinonen, M., et al., 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., et al., 2009. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360, 2416-2425.

Lequerre, T., Quartier, P., Rosellini, D., et al., 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.

McIntyre, K.W., Stepan, G.J., Kolinsky, K.D., et al., 1991. Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody. J Exp Med 173, 931-939.

Migkos, M.P., Somarakis, G.A., Markatseli, T.E., et al., 2015. Tuberculous pyomyositis in a rheumatoid arthritis patient treated with anakinra. Clin Exp Rheumatol 33, 734-736.

Schlesinger, N., Alten, R.E., Bardin, T., et al., 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.

Shuck, M.E., Eessalu, T.E., Tracey, D.E., et al., 1991. Cloning, heterologous expression and characterization of murine interleukin 1 receptor antagonist protein. Eur J Immunol 21, 2775-2780.

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