SNAPSHOT

AOP ID and Title:

Authors

Yutaka Kimura (1) Setsuya Aiba (1) 

(1) Depertment of Dermatology, Tohoku University Graduate School of Medicine

Corresponding author: Setsuya Aiba

Status

Abstract

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 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 plausibility that suppressed NF-kB activation leads to impaired T cell activation 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, tuberculosis or viral infection. 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

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). 

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

Events

Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO)

Key Event Relationships

Stressors

Overall Assessment of the AOP

Domain of Applicability

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

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). 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). 

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 (Fremond et al., 2004; Picard et al., 2010; Scanga et al., 2004; von Bernuth et al., 2008). 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).

Weight of Evidence Summary

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

Biological plausibility

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

IL-1α and IL-1β independently bind the type I IL-1 receptor (IL-1R1), which is ubiquitously expressed. The IL-1R3 (formerly IL-1R accessory protein (IL-1RAcP)) serves as a co-receptor that is required for signal transduction of IL-1/IL-1RI complexes.

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-1R3. 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. This is paralleled by the (auto)phosphorylation of IRAK4, which subsequently phosphorylates IRAK1 and IRAK2, and then this is followed by the recruitment and oligomerization of tumor necrosis factor–associated factor (TRAF) 6. Activation of NF-κB by IL-1 requires the activation of inhibitor of nuclear factor B (IκB) kinase 2 (IKK2). Activated IKK phosphorylates IκBα, which promotes its K48-linked polyubiquitination and subsequent degradation by the proteasome. IκB destruction allows the release of p50 and p65 NF-κB subunits and their nuclear translocation, which is the central step in activation of NF-κB. Both NF-κBs bind to a conserved DNA motif that is found in numerous IL-1–responsive genes. (Weber et al., 2010a, b)

Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation

In T lineage cells, the temporal regulation of NF-kb controls the stepwise differentiation and antigen-dependent selection of conventional and specialized subsets of T cells in response to T cell receptor and costimulatory, cytokines and growth factor signals. Cytokines include cytokines produced from macrophage or monocyte such as IL-1b. (Gerondakis et al., 2014)

Suppression of T cell activation leads to Increase, Increased susceptibility to infection

First type immunity drives resistance to viruses and intracellular bacteria, such as Listeria monocytogenes, Salmonella spp. and Mycobacteria spp., as well as to intracellular protozoan parasites such as Leishmania spp. The T helper 1 signature cytokine interferon-γ has a central role in triggering cytotoxic mechanisms including macrophage polarization towards an antimicrobial response associated with the production of high levels of reactive oxygen species and reactive nitrogen species, activation of CD8 cytotoxic T lymphocytes and natural killer cells to kill infected cells via the perforin and/or granzyme B-dependent lytic pathway or via the ligation of surface death receptors; and B cell activation towards the production of cytolytic antibodies that target infected cells for complement and Fc receptor-mediated cellular cytotoxicity.

Resistance to extracellular metazoan parasites and other large parasites is mediated and/or involves second type immunity. Pathogen neutralization is achieved via different mechanisms controlled by T 2 signature cytokines, including interleukin-4, IL-5 and IL-13, and by additional type 2 cytokines such as thymic stromal lymphopoietin, IL-25 or IL-33, secreted by damaged cell. T 2 signature cytokines drive B cell activation towards the production of high-affinity pathogen-specific IgG1 and IgE antibodies that function via Fc-dependent mechanisms to trigger the activation of eosinophils, mast cells and basophils, expelling pathogens across epithelia.

T17 immunity confers resistance to extracellular bacteria such as Klebsiella pneumoniae, Escherichia coli, Citrobacter rodentium, Bordetella pertussis, Porphyromonas gingivalis and Streptococcus pneumoniae, and also to fungi such as Candida albicans, Coccidioides posadasii, Histoplasma capsulatum and Blastomyces dermatitidis. Activation of T 17 cells by cognate T cell receptor (TCR–MHC class II interactions and activation of group 3 innate lymphoid cells (ILC3s) via engagement of IL-1 receptor (IL-1R) by IL-1β secreted from damaged cells lead to the recruitment and activation of neutrophils. T 17 immunopathology is driven to a large extent by products of neutrophil activation, such as ROS and elastase (reviewed by Soares et al. (Soares et al., 2017).

Based on these evidences, the insufficient T cell or B cell function causes impaired resistance to infection.

Empirical support

This table summarizes the empirical support obtained from the experiment using several inhibitor or gene targeting mice.  

Considerations for Potential Applications of the AOP (optional)

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

Alessiani, M., Kusne, S., Martin, M., Jain, A., Abu-Elmagd, K., Moser, J., Todo, S., Fung, J., Starzl, T., 1991. Infections in adult liver transplant patients under FK 506 immunosuppression. Transplant Proc 23, 1501-1503.

Arlt, A., Vorndamm, J., Breitenbroich, M., Folsch, U.R., Kalthoff, H., Schmidt, W.E., Schafer, H., 2001. Inhibition of NF-kappaB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin. Oncogene 20, 859-868.

Cassidy, J.P., R.: Laxer, R.; Lindsley, C, 2010. Textbook of Pediatric Rheumatology

6th Edition. Saunders.

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.

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

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.

Ekberg, H., Grinyo, J., Nashan, B., Vanrenterghem, Y., Vincenti, F., Voulgari, A., Truman, M., Nasmyth-Miller, C., Rashford, M., 2007. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR Study. Am J Transplant 7, 560-570.

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.

Fremond, C.M., Yeremeev, V., Nicolle, D.M., Jacobs, M., Quesniaux, V.F., Ryffel, B., 2004. Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88. J Clin Invest 114, 1790-1799.

Fung, J.J., Todo, S., Tzakis, A., Alessiani, M., Abu-Elmagd, K., Jain, A., Bronster, O., Martin, M., Gordon, R., Starzl, T.E., 1991. Current status of FK 506 in liver transplantation. Transplant Proc 23, 1902-1905.

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.

Gerondakis, S., Fulford, T.S., Messina, N.L., Grumont, R.J., 2014. NF-kappaB control of T cell development. Nat Immunol 15, 15-25.

Goh, A.X., Bertin-Maghit, S., Ping Yeo, S., Ho, A.W., Derks, H., Mortellaro, A., Wang, C.I., 2014. A novel human anti-interleukin-1beta neutralizing monoclonal antibody showing in vivo efficacy. MAbs 6, 765-773.

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.

Hannum, C.H., Wilcox, C.J., Arend, W.P., Joslin, F.G., Dripps, D.J., Heimdal, P.L., Armes, L.G., Sommer, A., Eisenberg, S.P., Thompson, R.C., 1990. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343, 336-340.

Hellerbrand, C., Jobin, C., Iimuro, Y., Licato, L., Sartor, R.B., Brenner, D.A., 1998. Inhibition of NFkappaB in activated rat hepatic stellate cells by proteasome inhibitors and an IkappaB super-repressor. Hepatology 27, 1285-1295.

Hoffman, H.M., Throne, M.L., Amar, N.J., Sebai, M., Kivitz, A.J., Kavanaugh, A., Weinstein, S.P., Belomestnov, P., Yancopoulos, G.D., Stahl, N., Mellis, S.J., 2008. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum 58, 2443-2452.

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.

Issafras, H., Corbin, J.A., Goldfine, I.D., Roell, M.K., 2014. Detailed mechanistic analysis of gevokizumab, an allosteric anti-IL-1beta antibody with differential receptor-modulating properties. J Pharmacol Exp Ther 348, 202-215.

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.

Lee, K.M., Kang, B.S., Lee, H.L., Son, S.J., Hwang, S.H., Kim, D.S., Park, J.S., Cho, H.J., 2004. Spinal NF-kB activation induces COX-2 upregulation and contributes to inflammatory pain hypersensitivity. Eur J Neurosci 19, 3375-3381.

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.

Lin, D., Lei, L., Zhang, Y., Hu, B., Bao, G., Liu, Y., Song, Y., Liu, C., Wu, Y., Zhao, L., Yu, X., Liu, H., 2015. Secreted IL-1alpha promotes T-cell activation and expansion of CD11b(+) Gr1(+) cells in carbon tetrachloride-induced liver injury in mice. Eur J Immunol 45, 2084-2098.

Mansouri, B., Richards, L., Menter, A., 2015. Treatment of two patients with generalized pustular psoriasis with the interleukin-1beta inhibitor gevokizumab. Br J Dermatol 173, 239-241.

Matsumoto, G., Namekawa, J., Muta, M., Nakamura, T., Bando, H., Tohyama, K., Toi, M., Umezawa, K., 2005. Targeting of nuclear factor kappaB Pathways by dehydroxymethylepoxyquinomicin, a novel inhibitor of breast carcinomas: antitumor and antiangiogenic potential in vivo. Clin Cancer Res 11, 1287-1293.

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.

Nambu, A., Nakae, S., Iwakura, Y., 2006. IL-1beta, but not IL-1alpha, is required for antigen-specific T cell activation and the induction of local inflammation in the delayed-type hypersensitivity responses. Int Immunol 18, 701-712.

Nishioka, C., Ikezoe, T., Jing, Y., Umezawa, K., Yokoyama, A., 2008. DHMEQ, a novel nuclear factor-kappaB inhibitor, induces selective depletion of alloreactive or phytohaemagglutinin-stimulated peripheral blood mononuclear cells, decreases production of T helper type 1 cytokines, and blocks maturation of dendritic cells. Immunology 124, 198-205.

Ohkusu-Tsukada, K., Ito, D., Takahashi, K., 2018. The Role of Proteasome Inhibitor MG132 in 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis in NC/Nga Mice. Int Arch Allergy Immunol 176, 91-100.

Orciuolo, E., Galimberti, S., Petrini, M., 2007. Bortezomib inhibits T-cell function versus infective antigenic stimuli in a dose-dependent manner in vitro. Leuk Res 31, 1026-1027.

Ortiz-Lazareno, P.C., Hernandez-Flores, G., Dominguez-Rodriguez, J.R., Lerma-Diaz, J.M., Jave-Suarez, L.F., Aguilar-Lemarroy, A., Gomez-Contreras, P.C., Scott-Algara, D., Bravo-Cuellar, A., 2008. MG132 proteasome inhibitor modulates proinflammatory cytokines production and expression of their receptors in U937 cells: involvement of nuclear factor-kappaB and activator protein-1. Immunology 124, 534-541.

Palombella, V.J., Rando, O.J., Goldberg, A.L., Maniatis, T., 1994. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 78, 773-785.

Parnet, P., Pousset, F., Laye, S., 2003. NF kappa B activation in mouse pituitary: comparison of response to interleukin-1 beta and lipopolysaccharide. J Neuroendocrinol 15, 304-314.

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

Roell, M.K., Issafras, H., Bauer, R.J., Michelson, K.S., Mendoza, N., Vanegas, S.I., Gross, L.M., Larsen, P.D., Bedinger, D.H., Bohmann, D.J., Nonet, G.H., Liu, N., Lee, S.R., Handa, M., Kantak, S.S., Horwitz, A.H., Hunter, J.J., Owyang, A.M., Mirza, A.M., Corbin, J.A., White, M.L., 2010. Kinetic approach to pathway attenuation using XOMA 052, a regulatory therapeutic antibody that modulates interleukin-1beta activity. J Biol Chem 285, 20607-20614.

Satou, Y., Nosaka, K., Koya, Y., Yasunaga, J.I., Toyokuni, S., Matsuoka, M., 2004. Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro. Leukemia 18, 1357-1363.

Scanga, C.A., Bafica, A., Feng, C.G., Cheever, A.W., Hieny, S., Sher, A., 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 Immun 72, 2400-2404.

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.

Seckinger, P., Kaufmann, M.T., Dayer, J.M., 1990a. 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. Immunobiology 180, 316-327.

Seckinger, P., Klein-Nulend, J., Alander, C., Thompson, R.C., Dayer, J.M., Raisz, L.G., 1990b. Natural and recombinant human IL-1 receptor antagonists block the effects of IL-1 on bone resorption and prostaglandin production. J Immunol 145, 4181-4184.

Settas, L.D., Tsimirikas, G., Vosvotekas, G., Triantafyllidou, E., Nicolaides, P., 2007. Reactivation of pulmonary tuberculosis in a patient with rheumatoid arthritis during treatment with IL-1 receptor antagonists (anakinra). J Clin Rheumatol 13, 219-220.

Sha, W.C., Liou, H.C., Tuomanen, E.I., Baltimore, D., 1995. Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell 80, 321-330.

Sigma-Aldrich, IL-1Ra Specification Sheet.

Soares, M.P., Teixeira, L., Moita, L.F., 2017. Disease tolerance and immunity in host protection against infection. Nat Rev Immunol 17, 83-96.

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.

Vallejo, S., Palacios, E., Romacho, T., Villalobos, L., Peiro, C., Sanchez-Ferrer, C.F., 2014. The interleukin-1 receptor antagonist anakinra improves endothelial dysfunction in streptozotocin-induced diabetic rats. Cardiovasc Diabetol 13, 158.

von Bernuth, H., Picard, C., Jin, Z., Pankla, R., Xiao, H., Ku, C.L., Chrabieh, M., Mustapha, I.B., Ghandil, P., Camcioglu, Y., Vasconcelos, J., Sirvent, N., Guedes, M., Vitor, A.B., Herrero-Mata, M.J., Arostegui, J.I., Rodrigo, C., Alsina, L., Ruiz-Ortiz, E., Juan, M., Fortuny, C., Yague, J., Anton, J., Pascal, M., Chang, H.H., Janniere, L., Rose, Y., Garty, B.Z., Chapel, H., Issekutz, A., Marodi, L., Rodriguez-Gallego, C., Banchereau, J., Abel, L., Li, X., Chaussabel, D., Puel, A., Casanova, J.L., 2008. Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321, 691-696.

Wang, Y., Sun, B., Volk, H.D., Proesch, S., Kern, F., 2011. Comparative study of the influence of proteasome inhibitor MG132 and ganciclovir on the cytomegalovirus-specific CD8(+) T-cell immune response. Viral Immunol 24, 455-461.

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.

Weih, F., Carrasco, D., Durham, S.K., Barton, D.S., Rizzo, C.A., Ryseck, R.P., Lira, S.A., Bravo, R., 1995. Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 80, 331-340.

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.

Yamada, H., Mizuno, S., Reza-Gholizadeh, M., Sugawara, I., 2001. Relative importance of NF-kappaB p50 in mycobacterial infection. Infect Immun 69, 7100-7105.

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.

Yu, A., Malek, T.R., 2001. The proteasome regulates receptor-mediated endocytosis of interleukin-2. J Biol Chem 276, 381-385.

Appendix 1

List of MIEs in this AOP

List of Key Events in the AOP

List of Adverse Outcomes in this AOP

Appendix 2

List of Key Event Relationships in the AOP