Impaired IL-1R1 signaling in T cell

1. Decreased IL-1 production

Decreased IL-1 production by macrophages or dendritic cells can be induced by suppressed IL-1β mRNA induction or suppressed maturation of pro-IL-1β. Dexamethasone is one of the representative drugs that significantly suppress IL-1β production from monocytes (Finch-Arietta and Cochran, 1991). Other than dexamethasone, the inhibition of various targets in different layers from the stimulation of PRRs or the receptors of proinflammatory cytokines lto the activation of NF-κB or the inhibition of posttranscriptional regulation of pro-IL-1β cause impaired IL-1R1 signaling. Among various PRRs, the signaling through TLR4 is best characterized. In addition, it is beyond the scope of this AOP to cover all signaling through each PRR. So, this AOP focuses on TLR4 signaling.

Lipopolysaccharide (LPS) from the bacteria binds to TLR4 in complex with myeloid differentiation factor-2 (MD2), and this complex initiates signalling by recruiting the adaptor proteins MyD88, TIR domain containing adaptor protein (TIRAP), TIR-domain-containing adapter-inducing interferon-β (TRIF) and TIR-domain containing adaptor (TRAM). MYD88 associates with IL‑1R‑associated kinase 1 (IRAK1) and IRAK4 and recruits TNFR-associated factor 6 (TRAF6). This complex recruits TGF-β-activated kinase 1 (TAK1), leading to phosphorylation of NF-κB inhibitor (IκB), activation of nuclear factor-κB (NF-κB) and consequent transcription of a range of genes coding for pro-inflammatory cytokines, including tumour necrosis factor (TNF), IL-6, pto-IL-1b, and pro-IL-18 (Mills, 2011).

Therefore, chemicals that affect the signaling pathway leading to the activation of these transcription factors are supposed to suppress IL-1β production. Among them, the chemical substances that affect NF-κB signaling have been investigated most thoroughly. Quite a few compounds have been reported to inhibit NF-κB signaling by several different mechanisms reviewed by Fuchs (Fuchs, 2010).  In fact, dimethyl fumarate inhibits the activation of NF‐κB, resulting in a loss of proinflammatory cytokine production, distorted maturation and function of antigen‐presenting cells, and immune deviation of T helper cells (Th) from the type 1 (Th1) and type 17 (Th17) profiles to a type 2 (Th2) phenotype (McGuire et al., 2016; Peng et al., 2012). Several studies have shown intriguing pharmacologic effects associated with curcumin, which inhibits NF-κB expression by regulating NF-κB/IκB pathway and down-regulates expression of pro-inflammatory cytokines, such as IL-1, IL-6, IL-8, and TNFα (Wang et al., 2018). Iguratimod, a methanesulfonanilide, that is a novel disease-modifying antirheumatic drug, inhibits NF-κB but not its inhibitor, IκBα, and inhibits the production of IL-1β (Mucke, 2012). Epigalocathechin gallate (EGCG) has been reported to inhibit NF-κB activation through inhibition of p65 phosphorylation (Wheeler et al., 2004) and suppress the production of LPS-stimulated IL-1β (Wang et al., 2020). DHMEQ inhibits lLPS-induced NF-κB activation by inhibiting its nuclear translocation from the cytoplasm. It also inhibits LPS-induced secretion of IL-1β (Suzuki and Umezawa, 2006).

Other than the inhibitors for NF-κB signaling, which can be stimulated by various stimulations other than TLR4 stimulation, there are signaling molecules that are specific to TLR4 signaling, such as TLR4, Mal, TRAM, Myd88, IRAK4, and IRAK1/2 (Vallabhapurapu and Karin, 2009). There are several chemicals that targe some of these molecules, an inhibitors of TLR4 such as TAK-242 (Matsunaga et al., 2011) and various IRAK4 inhibitors (Lee et al., 2017). IRAK4 has recently attracted attention as a therapeutic target for inflammation and tumor diseases.

Beside transcriptional regulation of IL-1β production, minocycline, and two prodrugs, pralnacasan (VX-740) and belnacasan (VX-765) that are orally absorbed and converted into the active principle, VRT-018858 and VRT-043198, respectively (Fenini et al., 2017) suppress IL-1 signaling by the inhibition of caspase-1 activation. Caspase-1 is an essential enzyme for maturation of pro- IL-1β and the secretion of mature IL-1β (Vincent and Mohr, 2007). Recently, it has been reported that cinnamicaldehyde suppresses serum IL-1β level in endotoxin poisoning mice (Xu et al., 2017).

2. Blocking of binding of IL-1 to IL-1R1

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-1R like rilonacept (Kapur and Bonk, 2009). The binding of IL-1β to IL-1R1 can be inhibited by anti-IL-1β antibody (canakinumab and gevokizumab) (Church and McDermott, 2009) (Roell et al., 2010).

This AOP focus on the blocking of binding of IL-1 to IL-1R1, and an inhibition or suppression of IL-1 signaling is out of scope, because the molecular initiating event of IL-1 blocking is simple and appropriate for developing AOP. This AOP is expected to be applicable to any chemicals which bind to IL-1R, although such stressor has not been reported.

1. Real time polymerase chain reaction to measure IL-1α or IL-1β mRNA
2. Enzyme-linked immunosorbent assay (ELISA) to detect IL-1α or IL-1 b protein
3. Competitive inhibition binding experiments using ¹²⁵I-IL-1α 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 (McIntyre et al., 1991; Shuck et al., 1991).
4. Measure the ability of the reagent to neutralize the bioactivity of human IL-1β on primary human fibroblasts in vitro(Alten et al., 2008)

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. Age-dependent difference in IL-1 signaling is not known.

The IL1B gene is conserved in human, chimpanzee, rhesus monkey, dog, cow, mouse, rat, and frog (https://www.ncbi.nlm.nih.gov/homologene/481), and the Myd88 gene is conserved in 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 lower level of stress-induced IL-1β expression is demonstrated in the aged murine keratinocytes (Pilkington et al., 2018).

The IL-1β production by mouse oral mucosal leukocytes stimulated with candida albicans was reduced with aging (Bhaskaran et al., 2020).

The baseline IL-1 signaling of the upper respiratory tract lavage was reduced in murine newborn mice (Kuipers et al., 2018).

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, 10.1186/ar2438

Bhaskaran, N., Faddoul, F., Paes da Silva, A., et al. (2020), IL-1beta-MyD88-mTOR Axis Promotes Immune-Protective IL-17A(+)Foxp3(+) Cells During Mucosal Infection and Is Dysregulated With Aging. Front Immunol 11: 595936, 10.3389/fimmu.2020.595936

Chaudhary, D., Robinson, S., Romero, D.L. (2015), Recent advances in the discovery of small molecule inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4) as a therapeutic target for inflammation and oncology disorders. J Med Chem 58: 96-110, 10.1021/jm5016044

Church, L.D., McDermott, M.F. (2009), Canakinumab, a fully-human mAb against IL-1beta for the potential treatment of inflammatory disorders. Curr Opin Mol Ther 11: 81-89,

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,

Fenini, G., Contassot, E., French, L.E. (2017), Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases. Front Pharmacol 8: 278, 10.3389/fphar.2017.00278

Finch-Arietta, M.B., Cochran, F.R. (1991), Cytokine production in whole blood ex vivo. Agents Actions 34: 49-52, 10.1007/BF01993235

Fuchs, O. (2010), Transcription factor NF-kappaB inhibitors as single therapeutic agents or in combination with classical chemotherapeutic agents for the treatment of hematologic malignancies. Curr Mol Pharmacol 3: 98-122, 10.2174/1874467211003030098

Ho, S.C., Chang, Y.H., Chang, K.S. (2018), Structural Moieties Required for Cinnamaldehyde-Related Compounds to Inhibit Canonical IL-1beta Secretion. Molecules 23, 10.3390/molecules23123241

Huang, H., Wang, Y. (2017), The protective effect of cinnamaldehyde on lipopolysaccharide induced acute lung injury in mice. Cell Mol Biol (Noisy-le-grand) 63: 58-63, 10.14715/cmb/2017.63.8.13

Jeon, Y.J., Han, S.H., Lee, Y.W., et al. (2000), Dexamethasone inhibits IL-1 beta gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-kappa B/Rel and AP-1 activation. Immunopharmacology 48: 173-183, 10.1016/s0162-3109(00)00199-5

Kapur, S., Bonk, M.E. (2009), Rilonacept (arcalyst), an interleukin-1 trap for the treatment of cryopyrin-associated periodic syndromes. P t 34: 138-141,

Klein, S.L., Flanagan, K.L. (2016), Sex differences in immune responses. Nat Rev Immunol 16: 626-638, 10.1038/nri.2016.90

Kuipers, K., Lokken, K.L., Zangari, T., et al. (2018), Age-related differences in IL-1 signaling and capsule serotype affect persistence of Streptococcus pneumoniae colonization. PLoS Pathog 14: e1007396, 10.1371/journal.ppat.1007396

Lee, K.L., Ambler, C.M., Anderson, D.R., et al. (2017), Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoli ne-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design. J Med Chem 60: 5521-5542, 10.1021/acs.jmedchem.7b00231

Matsunaga, N., Tsuchimori, N., Matsumoto, T., et al. (2011), TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Mol Pharmacol 79: 34-41, 10.1124/mol.110.068064

McGuire, V.A., Ruiz-Zorrilla Diez, T., Emmerich, C.H., et al. (2016), Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation. Sci Rep 6: 31159, 10.1038/srep31159

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,

Mills, K.H. (2011), TLR-dependent T cell activation in autoimmunity. Nat Rev Immunol 11: 807-822, 10.1038/nri3095

Morand, E.F., Rickard, D., Goulding, N.J. (1993), Lack of involvement of lipocortin 1 in dexamethasone suppression of IL-1 release. Mediators Inflamm 2: 49-52, 10.1155/S0962935193000067

Mucke, H.A. (2012), Iguratimod: a new disease-modifying antirheumatic drug. Drugs Today (Barc) 48: 577-586, 10.1358/dot.2012.48.9.1855758

Peng, H., Guerau-de-Arellano, M., Mehta, V.B., et al. (2012), Dimethyl fumarate inhibits dendritic cell maturation via nuclear factor kappaB (NF-kappaB) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen stress-activated kinase 1 (MSK1) signaling. J Biol Chem 287: 28017-28026, 10.1074/jbc.M112.383380

Pilkington, S.M., Ogden, S., Eaton, L.H., et al. (2018), Lower levels of interleukin-1beta gene expression are associated with impaired Langerhans' cell migration in aged human skin. Immunology 153: 60-70, 10.1111/imm.12810

Qiu, H.B., Pan, J.Q., Zhao, Y.Q., et al. (1997), Effects of dexamethasone and ibuprofen on LPS-induced gene expression of TNF alpha, IL-1 beta, and MIP-1 alpha in rat lung. Zhongguo Yao Li Xue Bao 18: 165-168,

Quartier, P. (2011), Interleukin-1 antagonists in the treatment of autoinflammatory syndromes, including cryopyrin-associated periodic syndrome. Open Access Rheumatol 3: 9-18, 10.2147/oarrr.S6696

Ravizza, T., Lucas, S.M., Balosso, S., et al. (2006), Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia 47: 1160-1168, 10.1111/j.1528-1167.2006.00590.x

Roell, M.K., Issafras, H., Bauer, R.J., et al. (2010), Kinetic approach to pathway attenuation using XOMA 052, a regulatory therapeutic antibody that modulates interleukin-1beta activity. J Biol Chem 285: 20607-20614, 10.1074/jbc.M110.115790

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, 10.1002/eji.1830211119

Stack, J.H., Beaumont, K., Larsen, P.D., et al. (2005), IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol 175: 2630-2634, 10.4049/jimmunol.175.4.2630

Suzuki, E., Umezawa, K. (2006), Inhibition of macrophage activation and phagocytosis by a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin. Biomed Pharmacother 60: 578-586, 10.1016/j.biopha.2006.07.089

Vallabhapurapu, S., Karin, M. (2009), Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 27: 693-733, 10.1146/annurev.immunol.021908.132641

van Furth, A.M., Seijmonsbergen, E.M., Langermans, J.A., et al. (1995), Effect of xanthine derivates and dexamethasone on Streptococcus pneumoniae-stimulated production of tumor necrosis factor alpha, interleukin-1 beta (IL-1 beta), and IL-10 by human leukocytes. Clin Diagn Lab Immunol 2: 689-692,

Vincent, J.A., Mohr, S. (2007), Inhibition of caspase-1/interleukin-1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes 56: 224-230, 10.2337/db06-0427

Wang, A.L., Yu, A.C., Lau, L.T., et al. (2005), Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 47: 152-158, 10.1016/j.neuint.2005.04.018

Wang, F., Han, Y., Xi, S., et al. (2020), Catechins reduce inflammation in lipopolysaccharide-stimulated dental pulp cells by inhibiting activation of the NF-kappaB pathway. Oral Dis 26: 815-821, 10.1111/odi.13290

Wang, Y., Tang, Q., Duan, P., et al. (2018), Curcumin as a therapeutic agent for blocking NF-kappaB activation in ulcerative colitis. Immunopharmacol Immunotoxicol 40: 476-482, 10.1080/08923973.2018.1469145

Weinberg, J.B., Mason, S.N., Wortham, T.S. (1992), Inhibition of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) messenger RNA (mRNA) expression in HL-60 leukemia cells by pentoxifylline and dexamethasone: dissociation of acivicin-induced TNF-alpha and IL-1 beta mRNA expression from acivicin-induced monocytoid differentiation. Blood 79: 3337-3343,

Wheeler, D.S., Catravas, J.D., Odoms, K., et al. (2004), Epigallocatechin-3-gallate, a green tea-derived polyphenol, inhibits IL-1 beta-dependent proinflammatory signal transduction in cultured respiratory epithelial cells. J Nutr 134: 1039-1044, 10.1093/jn/134.5.1039

Xu, F., Wang, F., Wen, T., et al. (2017), Inhibition of NLRP3 inflammasome: a new protective mechanism of cinnamaldehyde in endotoxin poisoning of mice. Immunopharmacol Immunotoxicol 39: 296-304, 10.1080/08923973.2017.1355377