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Impaired IL-1R1 signaling leads to Inhibition, Nuclear factor kappa B (NF-kB)
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Impaired IL-1R1 signaling leading to increased susceptibility to infection||adjacent||High||Moderate||Cataia Ives (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
|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
Mice lacking MYD88 or IRAK4 show severe defects in IL-1 signaling (Adachi et al., 1998; Medzhitov et al., 1998; Suzuki et al., 2002). Similarly, humans with mutations in the IRAK4 gene have defects in IL-1RI and Toll-like receptor (TLR) signaling (Picard et al., 2003).
Uncertainties and Inconsistencies
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.
Lye, E., Dhanji, S., Calzascia, T., Elford, AR., Ohashi, PA.. 2008. IRAK-4 kinase activity is required for IRAK-4-dependent innate and adaptive immune responses. Eur J Immunol. 38: 870-876/
Lye, E., Mirtos, C., Suzuki, N., Suzuki, S., Yeh, W-C. 2004. The role of interleukin 1 receptor-associated kinase-4 (IRAK-4) kinase activity in IRAK-4-mediated signaling. J Biol Chem. 279: 40653-40658.
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.