PR:000011406glucocorticoid receptorPR:000001753transcription factor NF-kappa-B subunitCL:0000542lymphocytePR:000003292NF-kappa-B inhibitorUBERON:0002405immune systemGO:0004883glucocorticoid receptor activityGO:0007249I-kappaB kinase/NF-kappaB signalingGO:0002534cytokine production involved in inflammatory responseGO:0007252I-kappaB phosphorylationD004198Disease SusceptibilityGO:0044414suppression of host defenses1increased2decreasedIL-1 receptor antagonist(IL-1Ra)(Anakinra)2019-06-01T00:37:572019-06-01T00:37:57anti-IL-1b antibody (Canakinumab)2019-06-01T00:38:212019-06-01T00:38:21soluble IL-1R (Rilonacept)2019-06-01T00:38:522019-06-01T00:38:529606Homo sapiens10090Mus musculus10116Rattus norvegicusActivation, Glucocorticoid ReceptorActivation, Glucocorticoid ReceptorMolecular<p><strong>Site of action:</strong> The molecular site of action is the glucocorticoid receptor (GR). The GR is a steroid receptor belonging to the nuclear receptor (NR) family of ligand-dependent transcription factors. In the absence of a ligand, the GR is transcriptionally inactive in the cytoplasm. <strong>Responses at the macromolecular level:</strong> Binding of a hormonal ligand enables GR to translocate into the nucleas where it binds to genomic GC-response elements (GRE) and regulates trascription of associated genes.</p>
<p>Glucocorticoid activation can be measured in a number of assays as stated by the EPA’s comptox dashboard (<a href="https://comptox.epa.gov/dashboard/assay_endpoints?search=NR3C1">https://comptox.epa.gov/dashboard/assay_endpoints?search=NR3C1</a>).</p>
<ul>
<li><a href="https://comptox.epa.gov/dashboard/assay_endpoints/ATG_GRE_CIS_up">ATG_GRE_CIS_up</a></li>
<li><a href="https://comptox.epa.gov/dashboard/assay_endpoints/ATG_GR_TRANS_up">ATG_GR_TRANS_up</a></li>
<li><a href="https://comptox.epa.gov/dashboard/assay_endpoints/NVS_NR_hGR">NVS_NR_hGR</a></li>
<li><a href="https://comptox.epa.gov/dashboard/assay_endpoints/TOX21_GR_BLA_Agonist_ratio">TOX21_GR_BLA_Agonist_ratio</a></li>
</ul>
<p>Receptor Transactivation Assays:</p>
<ul>
<li>Indigo Biosciences Human GR reporter assay system. Product Family IB0020 GR</li>
<li>Androgen receptor assays using adenoviral transduction of MMTV-luc reporter and/or hAR for endocrine screening of surface water samples (Hartig et al, 2002).</li>
</ul>
<p>In addition to invitro assay, induction of glucocorticoid receptor-regulated genes such as annexin a1b, gilz, glula, and fkbp1 are also indicative of GR activation in vivo (Garland et al., 2019).</p>
<p>Glucocorticoid receptor is fairly conserved across vertebrates. Fish however, have two copies of the gene resulting in two different receptors. Although conserved across species, the sensitivity of the glucocorticoid receptor varies based on species (Solte et al., 2006).</p>
<p> </p>
CL:0000255eukaryotic cellModerateMixedModerateAll life stages<p style="margin-left:0.5in">Garland MA, Sengupta S, Mathew LK, Truong L, Jong ED, Piersma AH, Du JL, Tanguay RL. 2019. <em>Glucocorticoid receptor-dependent induction of </em>cripto-1<em> (one-eyed pinhead) inhibits zebrafish caudal fin regeneration. </em>Toxicology Reports 6:529-537. https://doi.org/10.1016/j.toxrep.2019.05.013</p>
<p style="margin-left:0.5in">Solte EH, Lidy Verberg van Kemenade BM, Savelkoul FJ, Flik G. 2006. <em>Evolution of glucocorticoid receptors with different glucocorticoid sensitivity.</em> Journal of Endocrinology 190:17-28. DOI: 10.1677/joe.1.06703</p>
<p style="margin-left:0.5in">Medlock Kakaley EK, Blackwell BR, Cardon MC, Conley JM, Evans N, Feifarek DJ, Furlong ET, Glassmeyer ST, Gray LE Jr, Hartig PC, Kolpin DW, Mills MA, Rosenblum L, Villeneuve DL, Wilson VS. <em>De Facto Water Reuse: Bioassay suite approach delivers depth and breadth in endocrine active compound detection</em>. Sci Total Environ. 2020 Jan 10;699:134297. doi: 10.1016/j.scitotenv.2019.134297. Epub 2019 Sep 4. PubMed PMID: 31683213.</p>
<p>Conley JM, Lambright CS, Evans N, Strynar MJ, McCord J, McIntyre BS, Travlos GS, Cardon MC, Medlock-Kakaley E, Hartig PC, Wilson VS, Gray LE Jr. <em>Adverse Maternal, Fetal, and Postnatal Effects of Hexafluoropropylene Oxide Dimer Acid (GenX) from Oral Gestational Exposure in Sprague-Dawley Rats. Environ Health Perspect</em>. 2019 Mar;127(3):37008. doi: 10.1289/EHP4372. PubMed PMID: 30920876;PubMed Central PMCID: PMC6768323.</p>
<p>Medlock Kakaley E, Cardon MC, Gray LE, Hartig PC, Wilson VS. <em>Generalized Concentration Addition Model Predicts Glucocorticoid Activity Bioassay Responses to Environmentally Detected Receptor-Ligand Mixtures</em>. Toxicol Sci. 2019 Mar 1;168(1):252-263. doi: 10.1093/toxsci/kfy290. PubMed PMID: 30535411; PubMed Central PMCID: PMC6709530. </p>
<p>Conley JM, Evans N, Cardon MC, Rosenblum L, Iwanowicz LR, Hartig PC, Schenck KM, Bradley PM, Wilson VS. <em>Occurrence and In Vitro Bioactivity of Estrogen, Androgen, and Glucocorticoid Compounds in a Nationwide Screen of United States Stream Waters</em>. Environ Sci Technol. 2017 May 2;51(9):4781-4791. doi:10.1021/acs.est.6b06515. Epub 2017 Apr 12. PubMed PMID: 28401766. </p>
<p>Hartig PC, Bobseine KL, Britt BH, Cardon MC, Lambright CR, Wilson VS, Gray LE Jr. <em>Development of two androgen receptor assays using adenoviral transduction of MMTV-luc reporter and/or hAR for endocrine screening</em>. Toxicol Sci. 2002 Mar;66(1):82-90. PubMed PMID: 11861975.</p>
<p> </p>
2016-11-29T18:41:222020-07-07T12:19:59Inhibition, Nuclear factor kappa B (NF-kB)Inhibition, Nuclear factor kappa B (NF-kB)Molecular<p><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black">The NF-</span></span>κ<span style="font-size:12pt"><span style="color:black">B pathway consists of a series of events </span></span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">including IRAK (IL-1 receptor-associated kinase) signaling, </span></span></span><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black">where the transcription factors of the </span></span></span><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span></span></span><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black"> family play the key role. The canonical</span></span></span><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black"> NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span></span></span><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black"> pathway can be activated by a range of stimuli, including TNF receptor activation by TNF-a. Upon pathway activation, the IKK complex will be phosphorylated, which in turn phosphorylates IkBa. This </span></span></span><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span></span></span><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black"> inhibitor will be K48-linked ubiquitinated and degradated, allowing </span></span></span><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span></span></span><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black"> to translocate to the nucleus. There, this transcription factor can express pro-inflammatory and anti-apoptotic genes. Furthermore, negative feedback genes are also transcribed and include IkBa and A20. When the </span></span></span><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span></span></span><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black"> pathway is inhibited, its translocation will be delayed (or absent), resulting in less or no regulation of </span></span></span><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span></span></span><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black"> target genes. This can be achieved by IKK inhibitors, proteasome inhibitors, nuclear translocation inhibitors or DNA-binding inhibitors (Gupta et al., 2010; Liu et al., 2017). Therefore, inhibition of IL-1R activation suppresses </span></span></span><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span></span></span><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black">.</span></span></span></p>
<p> </p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック""><span style="font-family:"Times New Roman",serif"><span style="color:black">In addition to the NF-</span></span><span style="font-family:Symbol"><span style="color:black">k</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B pathway, IRAK activates a variety of transcription factors, including Interferon regulatory factor 5 (IRF5), Adaptor protein-1 (AP-1) and cAMP response element binding protein (CREB), resulting in the expression of broad array of inflammatory molecules and apoptosis-related proteins (Jain, 2014).</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B transcriptional activity: Beta lactamase reporter gene assay (Miller et al. 2010)</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κB transcription: Lentiviral NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">BGFP reporter with flow cytometry (Moujalled et al. 2012)</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">I</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">α</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black"> phosphorylation: Western blotting (Miller et al. 2010)</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:Times"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:Times"><span style="color:black">B p65 (Total/Phospho) ELISA</span></span><span style="color:black">:</span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">ELISA for IL-6, IL-8, and Cox</span></span></span></span></p>
<p><span style="font-family:Times New Roman,Times,serif">The binding of sex steroids to their respective steroid receptors directly influences NF-κB signaling, resulting in differential production of cytokines and chemokines (McKay and Cidlowski, 1999; Pernis, 2007). 17b-estradiol regulates pro-inflammatory responses that are transcriptionally mediated by NF‑κB through a negative feedback and/or transrepressive interaction with NF-κB (Straub, 2007). Progesterone suppresses innate immune responses and NF-κB signal transduction reviewed by Klein et al. (Klein and Flanagan, 2016). Androgen-receptor signaling antagonises transcriptional factors NF-κB(McKay and Cidlowski, 1999).</span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><strong><span style="font-family:"Times New Roman",serif"><span style="color:black">Evidence for perturbation of this molecular initiating event by stressor</span></span></strong></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">Dex inhibits IL-1β gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B/Rel and AP-1 activation</span></span> <span style="font-family:"Times New Roman",serif"><span style="color:black">(Jeon et al., 2000)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">Various inhibitors for NF‐κB, such as dimethyl fumarate, </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">curcumin, iguratimod, epigalocathechin gallate (</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">EGCG), and DHMEQ inhibits lLPS-induced NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B activation and LPS-induced secretion of IL-1</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">β</span></span> <span style="font-family:"Times New Roman",serif"><span style="color:black">(McGuire et al., 2016; Mucke, 2012; Peng et al., 2012; Suzuki and Umezawa, 2006; Wang et al., 2020; Wang et al., 2018; Wheeler et al., 2004)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">TAK-242 </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Matsunaga et al., 2011)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black"> inhibit TLR4 itself. There are several IRAK4 inhibitors </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Lee et al., 2017). These molecules block the upstream signal to NF‐κB activation. IRAK4 has recently attracted attention as a therapeutic target for inflammation and tumor diseases (Chaudhary et al., 2015)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">LPS treatment induced a significant upregulation of the mRNA and release of IL-1β from retinal microglia. Minocycline inhibited its releases. Thus, minocycline might exert its antiinflammatory effect on microglia by inhibiting the expression and release of IL-1β </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Wang et al., 2005)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">Caspase-1 inhibition reduced the release of IL-1β in organotypic slices exposed to LPS+ATP. Administration of pralnacasan (intracerebroventricular, 50 μg) or </span></span><span style="font-family:Times"><span style="color:black">belnacasan</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black"> (intraperitoneal, 25–200 mg/kg) to rats blocked seizure-induced production of IL-1β in the hippocampus, and resulted in a twofold delay in seizure onset and 50% reduction in seizure duration </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Ravizza et al., 2006)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span><span style="font-family:Times"><span style="color:black">elnacasan</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">, an orally active IL-1β converting enzyme/caspase-1 inhibitor, blocked IL-1β secretion with equal potency in LPS-stimulated cells from familial cold urticarial associated symdrome and control subjects </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Stack et al., 2005)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">In LPS-induced acute lung injury (ALI) mice model, LPS induced inflammatory cytokines such as TNF-α, IL-6, IL-13 and IL-1β were significantly decreased by cinnamaldehyde (CA) </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Huang and Wang, 2017)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">The suppressing capacities of six cinnamaldehyde-related compounds were evaluated and compared by using the LPS-primed and ATP-activated macrophages. At concentrations of 25~100 </span></span><span style="font-family:Symbol"><span style="color:black">m</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">M, cinnamaldehyde and 2-methoxy cinnamaldehyde dose-dependently inhibited IL-1β secretion </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Ho et al., 2018)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">In vitro, CA decreased the levels of pro-IL-1β and IL-1β in cell culture supernatants, as well as the expression of NLRP3 and IL-1β mRNA in cells. In vivo, CA decreased IL-1β production in serum. Furthermore, CA suppressed LPS-induced NLRP3, p20, Pro-IL-1β, P2X7 receptor (P2X7R) and cathepsin B protein expression in lung, as well as the expression of NLRP3 and IL-1β mRNA </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Xu et al., 2017)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">IL-1Ra binds IL-1R but does not initiate IL-1 signal transduction </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Dripps et al., 1991)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">. 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 </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Kapur and Bonk, 2009)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">. The binding of IL-1β to IL-1R1 can be inhibited by anti-IL-1β antibody (canakinumab and gevokizumab)</span></span> <span style="font-family:"Times New Roman",serif"><span style="color:black">(Church and McDermott, 2009)</span></span> <span style="font-family:"Times New Roman",serif"><span style="color:black">(Roell et al., 2010)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">IL-1 is known to mediates autoinflammatory syndrome, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever. Blocking of binding of IL-1 to IL-1R1 by anakinra, canakinumab, and rilonacept have been already used to treat these autoinflammatory syndrome associated with overactivation of IL-1 signaling </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Quartier, 2011)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">. </span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">Dex inhibits IL-1</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">β</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black"> gene expression in LPS-stimulated RAW 264.7 cells by blocking NF‐κB/Rel and AP-1 activation</span></span> <span style="font-family:"Times New Roman",serif"><span style="color:black">(Jeon et al., 2000)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">Inhibition of IL-1 binding to IL-1R or the decreased production of IL-1b leads to the suppression of IL-1R signaling leading to NF‐κB activation.</span></span></span></span></p>
<p><!--![endif]----><!--![endif]----></p>
UBERON:0002405immune systemCL:0000084T cellHighUnspecificHighAll life stagesHighHighHigh<p><span style="font-size:12pt"><span style="font-family:"Abadi MT Condensed Extra Bold",sans-serif"><span style="font-family:"Times New Roman",serif">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.<em> J Med Chem</em> 58: 96-110, 10.1021/jm5016044</span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Abadi MT Condensed Extra Bold",sans-serif"><span style="font-family:"Times New Roman",serif">Church, L.D., McDermott, M.F. (2009), Canakinumab, a fully-human mAb against IL-1beta for the potential treatment of inflammatory disorders.<em> Curr Opin Mol Ther</em> 11: 81-89, </span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Abadi MT Condensed Extra Bold",sans-serif"><span style="font-family:"Times New Roman",serif">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.<em> J Biol Chem</em> 266: 10331-10336, </span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Abadi MT Condensed Extra Bold",sans-serif"><span style="font-family:"Times New Roman",serif">Gupta, S.C., Sundaram, C., Reuter, S., et al. (2010), Inhibiting NF-kappaB activation by small molecules as a therapeutic strategy.<em> Biochim Biophys Acta</em> 1799: 775-787, 10.1016/j.bbagrm.2010.05.004</span></span></span></p>
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2016-11-29T18:41:232023-03-02T01:58:01Suppression, Inflammatory cytokinesSuppression, Inflammatory cytokinesIndividual2016-11-29T18:41:232016-12-03T16:37:49Decreased, LymphocytesDecreased, LymphocytesIndividual2016-11-29T18:41:232016-12-03T16:37:49Induction, IKB inhibitory proteinInduction, IKB inhibitory proteinCellularCL:0000255eukaryotic cell2016-11-29T18:41:232017-09-16T10:14:28Increased, Disease susceptibilityIncreased, Disease susceptibilityIndividual2016-11-29T18:41:242016-12-03T16:33:25Suppression, Immune systemSuppression, Immune systemIndividual2016-11-29T18:41:242016-12-03T16:37:497789bb25-31dd-4a0f-8a29-010f0f52235fd9c7aa3a-a32a-41b3-93fb-16ad0c33386a2016-11-29T18:41:332016-12-03T16:37:56d9c7aa3a-a32a-41b3-93fb-16ad0c33386a575027a8-ff2e-4c64-b36c-76759326187b2016-11-29T18:41:332016-12-03T16:37:56575027a8-ff2e-4c64-b36c-76759326187b37d200ac-5082-494d-955d-fffa6dc48cc42016-11-29T18:41:332016-12-03T16:37:5637d200ac-5082-494d-955d-fffa6dc48cc4b69b2ea9-4291-4a2d-84c7-0c97136dac082016-11-29T18:41:332016-12-03T16:37:56b69b2ea9-4291-4a2d-84c7-0c97136dac08b2789016-2c3a-4432-8bc7-18904ef0dd4d2016-11-29T18:41:332016-12-03T16:37:56Glucocorticoid Receptor Activation Leading to Increased Disease SusceptibilityGlucocorticoid Receptor, Activation<p>Carlie A. LaLone, University of Minnesota, Water Resources Center, lalone.carlie@epa.gov</p>
Open for comment. Do not cite1.29adjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot Specified2016-11-29T18:41:162023-04-29T16:02:55