IndraLab
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"One study reported direct binding of IL-1β to integrin α5β1 xref , however our data suggest activation of α5β1 is likely to occur downstream of IL-1β binding to IL-1R. Prior blocking of IL-1R prevented an increase in vinculin adhesion contacts and prevented the increase in α5β1 localizations and clustering at the membrane."
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"Both IL-1alpha and IL-1beta interact with the IL-1 receptor 1 (IL-1R1) and recruit the IL-1 receptor accessory protein (IL-1R3, formerly IL-1RAcP) to induce a downstream signal via several inflammatory kinases, such as Myd88, ERK, JNK and NFkappaB, leading to transcription of inflammatory, catabolic genes [XREF_BIBR - XREF_BIBR]."
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"Because corticosteroids are well-known to induce IL-1 Receptor Antagonist (IL-1RA) transcription (Levine et al., 1996), which binds to both IL-1α and IL-1β, we believed that the administration of corticosteroids was able to reduce IL-1α release, which we demonstrated to be responsible for TGF-β release during the exacerbation phase of COPD (Colarusso et al., 2019)."
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"Binding of IL-1β to IL-1R1 results in myeloid differentiation primary response protein 88 (MyD88)-dependent and MyD88-independent pathway activation, including induction of c-Jun N-terminal kinase (JNK), p38 MAPK, and NFκB, thus modulating proliferation, cell survival, apoptosis, and immune responses [ xref , xref ]."
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"The increase in IL-1beta levels after one to three hours and in TNF-alpha levels after prolonged incubation with A. actinomycetemcomitans infected macrophages possibly indicated that the binding of IL-1beta to its receptor IL-1R1 led to a cascade of downstream events, eventually resulting in the expression of TNF-alpha."
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"IL-1β interacts with IL-1R and activates NF-κB to promote a wide range of biological effects capable of inducing morphological and phenotypic transdifferentiation of tubular epithelial cells into myofibroblast-like cells (Gasse et al. xref ; Stewart and Marsden xref ; Vesey et al. xref )."
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"IL-1β signaling can be blocked by the decoy receptor IL1R2 either by preventing the interaction of IL-1β with IL1R1 through competitive binding [ xref , xref ] or by decreasing the concentration of IL1RAP, which is an essential member of the signaling complex, by forming a non-signaling complex with IL-1β and IL1R2 [ xref , xref ] ( xref and xref )."
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"IL-1α, and IL-1β bind IL-1R1, IL-33 binds ST2, IL-18 and IL-37 bind IL-18Ra, IL-37 also binds a decoy receptor IL-1R8 through which it mediates some anti-inflammatory activity, and the IL-36 cytokines all bind IL-36R.
All IL-1 family cytokines are expressed, with some variation, within the skin."
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"Canakinumab Biologic Inhibits binding of IL-1β to IL-1R1 [49] Anakinra Biologic Binds to IL-1 receptor to inhibit IL-1β binding [125] MCC950 Small molecule Inhibits caspase-1 activation by binding to NLRP3 [126] CY-09 Small molecule Inhibits NLRP3 ATPase activity by binding to the ATP-binding motif of the NACHT domain [127] Tranilast Small molecule Suppresses NLRP3 assembly by binding to NACHT domain [128] IC-100 Biologic Inhibits adaptor ASC [130] Argablin Small molecule Inhibits NLRP3 activation (specific mechanism not known) [129] Cholchicine Small molecule Inhibits expression of components of NLRP3 [113] IL-1β-interleukin-1beta; IL-1R1-interleukin 1 receptor 1; NLRP3-NLR family pyrin domain containing 3; ATP-adenosine triphosphate; NACHT-a central nucleotide-binding and oligomerization domain; ASC-Apoptosis-associated speck-like protein containing a caspaserecruitment domain."
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"In response to IL1beta binding to IL1R1, a complex sequence of combinatorial phosphorylation and ubiquitination events results in activation of nuclear factor kappaB (NF-kappaB) signaling and the JNK and p38 mitogen activated protein kinase pathways, which cooperatively induce the expression of canonical IL1beta target genes (such as IL-6, CXCL8, CCL2, COX-2, IkappaBalpha, IL1alpha, IL1beta, MKP-1) via transcriptional and post-translational modifications."
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"Typically, toll-like receptor stimulation in response to microbial infection results in binding of IL-1β to the IL-1R1 and leads to activation of: nuclear factor κ B (NFκB), p38 mitogen-activated protein kinase (p38 MAPK) as well as other kinases, and the hypothalamic pituitary-adrenal (HPA) axis."
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"IL-1β binds to its receptor IL-1R and recruits myeloid differentiation primary response protein MyD88 and IL-1R–associated kinase 4 (Irak4) to phosphorylate Irak1, enabling transient recruitment of TNF receptor–associated factor 6, dissociation of Irak1 from the receptor, and activation of Tak1 (49)."
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"Attenuation but not complete elimination of IL-1beta induced FGF2 expression and enhanced cell migration by sulfasalazine, a NF-kappaB inhibitor, and SB203580, an AP-1 inhibitor, showed that IL-1beta binding to IL-1R1 led to a parallel activation of AP-1 and NF-kappaB in human CEC."
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"Previous studies reported that IL1beta and TNFalpha exert toxic effects by binding to their cognate receptors, IL1-R1 and TNFR1, respectively, triggering downstream signaling pathways that activate transcription factors, such as NFkappaB or AP1 which in turn lead to the production of NO and ROS."
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"It is known that TLR and the interleukin-1 receptor (IL-1R) superfamily share a conserved cytoplasmic domain and that the binding of IL-1β to IL-1R induces activation of NF-κB and mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38), through the interaction between the TIR domain and MyD88 xref , xref ."
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"Alternatively, IL-1β–IL-1R interactions could be targeted therapeutically, as we described with the use of anakinra (IL-1R inhibitor) and neutralizing antibodies against IL-1β, to serve the dual purpose of not only preserving endothelial integrity ( xref ), but also attenuating the recruitment of inflammatory splenic monocytes."
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"Regardless of the intracellular signaling mechanisms, the primary outcome of inflammasome activation is the activation of caspase-1 and cleavage of pro-IL-1beta to IL-1beta, which binds to the IL-1R, and stimulates hepatic recruitment of IL-1R expressing cells, resulting in inflammation."
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"Collectively, these data show that a factor or factors released into the media of human placental explants prime monocytes for inflammasome induction.To determine whether IL-1β constitutively secreted by placental trophoblasts is responsible for the CM-mediated inflammasome priming in monocytes, we used an antibody that blocks binding of IL-1β to IL-1R and also generated THP-1 cells lacking expression of IL-1R through CRISPR-mediated gene editing (Fig. S3 G)."
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"Likewise, culture of stage 3 iNK cells in the continuous presence of a 100-fold molar excess of IL-1 receptor antagonist (IL-1RA), a naturally occurring specific competitive inhibitor of IL-1beta binding to IL-1R1, completely abrogated the IL-1beta-mediated expansion observed earlier (XREF_FIG)."
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"It is known that TLR and the interleukin-1 receptor (IL-1R) superfamily share a conserved cytoplasmic domain and that the binding of IL-1beta to IL-1R induces activation of NF-kappaB and mitogen activated protein kinases (MAPKs), including extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen activated protein kinase (p38), through the interaction between the TIR domain and MyD88 XREF_BIBR, XREF_BIBR."
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"Clearly, these conflicting studies around IL-1β indicate a need for more research dedicated to understanding the key cellular players and cellular signaling events involved in IL-1β-IL-1R signal-mediated atherosclerotic calcification both in the presence and absence of statin therapy, as overlapping pathways albeit with some likely variations analogous to the changes we identified with regard to ROS may be involved."
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"XREF_BIBR, XREF_BIBR, XREF_BIBR Binding of IL-1alpha or IL-1beta to IL1R1 leads to the activation of a series of protein kinases that subsequently trigger an increase in the expression of numerous pro inflammatory genes, XREF_BIBR, XREF_BIBR and in some cells triggers apoptosis, XREF_BIBR, XREF_BIBR likely depending on the local concentration of IL-1alpha and IL-1beta."
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"Therefore, one can hypothesize that the activity of the SNPs in this haplotype, or an unmeasured SNP (s) in linkage disequilibrium, decreases IL1R2 expression, which would increase the amount of pro inflammatory IL1-beta bound to IL1R1 and result in higher levels of trait and state anxiety."
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"Binding of IL-1β to endothelial IL-1R1 activates endothelial cells and triggers the up-regulation of cell adhesion molecules such as endothelial cell selectin (E-selectin) and intercellular adhesion molecule 1 (ICAM-1), pro-inflammatory cytokines such as IL-6 and TNF, and chemokines such as CXCL1, CXCL2, CXCL8, CX 3 CL1 and CXCL12 ( xref , xref - xref )."
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"IL-1a, and IL-1b bind IL-1R1, IL-33 binds ST2, IL-18 and IL-37 bind IL-18Ra, IL-37 also binds a decoy receptor IL-1R8 through which it mediates some anti-inflammatory activity, and the IL-36 cytokines all bind IL-36R.All IL-1 family cytokines are expressed, with some variation, within the skin."
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"IL-1alpha and IL-1beta bind to IL-1R1 and use IL-1RAcP as a common coreceptor and then recruit intracellular signaling molecules, including myeloid differentiation factor 88, IL-1R-associated kinase, and TNF receptor associated factor 6 (TRAF6) to activate nuclear factor-kappaB, as well as extracellular signal regulated kinase 1/2, c-Jun N-terminal kinase, and p38 MAPK 42."
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"The attendant cytokine recognition and assembly mechanisms of IL-1 receptors were only partly disclosed by the structure of the IL-1beta and IL-1R1 heterodimer complex, which further left open the inviting prospect of a face-to-face (or pseudosymmetric) docking of the unseen IL-1RAcP co-receptor chain."
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"RNA sequencing, quantitative real-time PCR, western blot, immunohistochemistry, RNAscope ISH, pharmacologic and genetic approaches were performed to examine the roles of spinal NLRP3 (The NOD-like receptor family, pyrin containing domain 3) inflammasome activation and IL-1β-IL1R1 signaling in chronic itch."
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"Furthermore, CD117 + cells, which co-express CD161 and IL-22, and thus correspond to the IL-1R1 hi subpopulation of stage 3 iNK cells, reside in the lamina propria and parafollicular T cell-rich area of human tonsil, and co-localized with a cellular source of IL-1β found in CD11c hi cDCs, attesting to the physiologic relevance of the IL-1β-IL-1R1 interaction in vivo ."
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"These pro-inflammatory cytokines, IL-6 and IL-8, can be produced by IL-1β stimulation in human GFs and PDLs.IL-1β is an important target in the regulation of inflammation-related diseases; there have been numerous studies regarding small molecules that affect IL-1 signaling by hindering the interactions between IL-1β and IL-1R [2,17,32,33,34]."
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"Because mice deficient in the IL-1R cannot respond to IL-1, this result demonstrated that either IL-1α or IL-1β, both of which bind to the IL-1R, contributed to acute pathology after rVSV immunization.Both IL-1α and IL-1β are regarded as pro-inflammatory cytokines, but IL-1β rather than IL-1α has been more commonly associated with symptoms such as weight loss and fever that are induced by infection with a live virus or other immune stimulus [16], [17]."
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"Additionally, the anti-inflammatory effect of BM-MSCs was confirmed in our patients by an increased level of the interleukin 1 receptor antagonist (IL-1Ra), a naturally-occurring cytokine that inhibits the binding of IL-1β to IL-1R. Muscle inflammation in DMD is primarily mediated by the IL-1β pathway, and the inhibition of its activity may potentially decrease inflammatory effects (the anti-inflammatory properties of IL-Ra were proved in the mdx mouse model through a functional improvement of the dystrophic muscle) [ xref ]."
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"The great abundance of IL1B, IL1R1, and IL1RAP and low abundance of IL1RN at the maternal-conceptus interface during the implantation period suggest that endometrial IL1R1 and IL1RAP expression is regulated by factors of conceptus origin, such as estrogen and IL1B, and that IL1B secreted by the conceptus plays a critical role in implantation by binding to IL1R1 and IL1RAP on the uterine endometrium."
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"Induction of cytokine signaling requires two types of receptors, a primary specific receptor, called IL-1 receptor Type I (IL-1RI) for IL-1b signaling, and an accessory receptor, called Il-1R accessory protein (IL-1RAcP) also binding IL-1b, that can be shared in some cases [55] ."
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"Anakinra is a recombinant form of the IL-1 receptor antagonist, which, similarly to its endogenous analog, is able to competitively inhibit the binding of IL-1β to its receptor IL1R. This drug has been used successfully in numerous autoimmune and auto-inflammatory conditions, including cytokine release syndrome (CRS) secondary to CAR-T cell therapy and HLH [ xref , xref , xref ]."
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"IL-1α, and IL-1β bind IL-1R1, IL-33 binds ST2, IL-18 and IL-37 bind IL-18Ra, IL-37 also binds a decoy receptor IL-1R8 through which it mediates some anti-inflammatory activity, and the IL-36 cytokines all bind IL-36R.All IL-1 family cytokines are expressed, with some variation, within the skin."
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"Myeloid Differentiation Primary Response 88 (Myd88) is a significant constituent of the signalling cascade downstream of IL-1β-IL-1R interaction, which ultimately converges with the canonical NF-κB signalling pathway leading to the further amplification of the inflammatory mediator production in RA ( xref ; xref )."
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"The increase in IL-1β levels after one to three hours and in TNF-α levels after prolonged incubation with A. actinomycetemcomitans- infected macrophages possibly indicated that the binding of IL-1β to its receptor IL-1R1 led to a cascade of downstream events, eventually resulting in the expression of TNF-α."
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"The IL-1 pathway is triggered when the ligands IL-1alpha and IL-1 beta (IL-1beta) bind to IL-1 receptor type I (IL-1R1) that forms a complex with the IL-1 receptor accessory protein (IL-1RAcP) and then recruits myeloid differentiation primary response gene 88 (MyD88), IL-1 receptor associated kinases (IRAKs), and TRAF6 [XREF_BIBR]."
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"Binding of IL-1beta to IL-1R elicits transduction signaling that activates nuclear factor kappa B (NF-kB) and mitogen activated protein kinase (MAPK) pathways to promote production of itself as well as induce expression of other proinflammatory cytokines like TNFalpha and IL-6 [XREF_BIBR]."
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"Although aged skin did show a greater induction of IL1R2 gene expression in response to both IL-1beta and TNF-alpha, suggesting that under inflammatory conditions IL-1beta signalling may be further suppressed due to greater availability of the IL-1R2 decoy receptor, which reduces IL-1beta binding to IL-1R1 and sequesters IL-1RAP.34 In aged skin the addition of recombinant IL-1beta protein may provide a large enough signal to induce IL1B gene expression in the target cell, and/or may bypass the need for de novo IL-1beta synthesis."
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"For example, in neurons, binding of IL-1β with IL-1R causes the recruitment of the neuron specific adaptor protein AcPb ( xref ) which mediates NDMR 2b phosphorylation, calcium influx, and excitotoxicity ( xref ); a potential mechanism linking IL-1β overproduction with exacerbated seizures ( xref )."
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"These data indicated that DS may inhibit the activation of NLRP3 inflammasome signaling via inducing mitophagy in CCI-induced neuropathic mice, thereby reducing the pain signal conduction caused by the binding of IL-1β to IL-1R on the spinal dorsal horn neurons, therefore raising the pain threshold."
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"The AT1 population expressed high levels of genes Developmental growth Circulatory-system process Regulation of haemopoiesis -log 10 P -log 10 P
Scaled gene expression T IL1R inhibitor-IL1B IL1R-IL1B IL1B-ADRB2 IL6R-IL6 IL6-HRH1 TGFB1-aVb6 complex TGFB1-TGFBR1 TGFB1-TGFBR2 TGFB1-TGFBR3 TGFB2-TGFBR1 TGFB2-TGFBR2 TGFB2-TGFBR3 TGFB3-TGFBR1 TGFB3-TGFBR2 TGFB3-TGFBR3 EGFR-TGFA EGFR- in the lungs of patients with COVID-19 ( Fig. 5e and Supplementary Table 4 )."
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"This mode of activation is somewhat similar to that of mammalian IL-1R. The expression of pro-IL-1β is induced by PAMPs and pro-IL-1β is proteolytically cleaved by Caspase-1 or Caspase-4/11 leading to the release of mature IL-1β that can bind IL-1R. However, there is no evidence that mammalian TLRs are activated by PAMPs through protein ligands analogeous to Drosophila spatzel."
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"Both PA401 and HuMax-IL8 have not been evaluated in patients with COPD.The IL-1 family consists of two related polypeptides, IL-1α and IL-1β that bind to the same primary receptor IL-1R1, which is expressed by almost all cell types, and can recruit and/or activate a variety of immune cells and immunocompetent cells, such as macrophages, endothelial cells, neutrophils, and epithelial cells."
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"As building block components of the respective complexes, we took the crystal structure of the IL-1beta and IL-1R1 complex and the calculated model of the IL-33 and ST2 complex, together with the common subunit, a homology model of the co-receptor (also built on the IL-1R1 template)."
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"During infection, mucosal injury and stress, the activation of IL-1beta can trigger local mucosal immune responses, by stimulating T cell proliferation, and direct neutrophils to injury or infection site through the combination of IL-1beta and IL-1R complexes, and further activate NF-kappaB and MAPK pathways, leading to the upregulation of other pro inflammatory cytokines and chemokines (such as IL-6, IL-8, and TNF)."
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"Another opportunity to block neutrophil hyperactivation is acting on IL-1beta and IL-1R interaction; anakinra (IL-1R inhibitor) is currently under clinical investigation showing promising preliminary results, whereas canakinumab (IL-1beta inhibitor) failed to ameliorate the outcome of severe COVID-19 patients (https://www.novartis.com/news/media-releases/novartis-provides-update-can-covid-trial-hospitalized-patients-covid-19-pneumonia-and-cytokine-release-syndrome-crs)."
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"Several mechanisms exist for negatively regulating IL-1RI signalling, including IL-1RII that binds both IL-1alpha and IL-1beta and acts as a decoy receptor, and IL-1Ra that serves as an endogenous competitive inhibitor of IL-1alpha and IL-1beta by binding but not activating IL-1RI."
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"Casadio et al. showed that an antibody directed against residues in the beta6-beta7 turn and strand beta7 of IL-1beta (residues 73-81) did not inhibit the biological effect of IL-1beta in cell based assays, thus disfavoring their computationally derived ' front ' model for the interaction of IL-1RAcP with the IL-1beta and IL-1R1 complex."
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"We have previously demonstrated that adoptive transfer of purified microglia from hTau- Cx3cr1 – / – mice that exhibit a highly inflammatory phenotype, into the brains of non-transgenic recipient mice was sufficient to induce tau pathology in a manner dependent upon IL-1β-IL-1R axis ( xref )."
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"Binding of IL-1β to IL-1R elicits transduction signaling that activates nuclear factor kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) pathways to promote production of itself as well as induce expression of other proinflammatory cytokines like TNFα and IL-6 [ xref ]."
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"Likewise, culture of stage 3 iNK cells in the continuous presence of a 100-fold molar excess of IL-1 receptor antagonist (IL-1RA), a naturally occurring specific competitive inhibitor of IL-1β binding to IL-1R1 ( xref ), completely abrogated the IL-1β-mediated expansion observed earlier ( xref )."
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"IL-1alpha and IL-1beta bind the same receptor, IL-1R1, and share similar proinflammatory properties mainly through the induction of cyclooxygenase type-2, type 2 phospholipase A, and inducible nitric oxide synthase, leading to recruitment of myeloid cells, including neutrophils, to sites of inflammation 16."
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"It is also relevant to note that the rapid translocation of RAGE to the cell surface during inflammatory activation is partly under NF-kB control [ xref , xref ] which is signalled via both the TLR4 and IL-1β-IL-1R pathways to MyD88, adding a further amplification pathway to that of RAGE-mediated uptake with further inflammasome release and pyroptosis."
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"The interleukin (IL)-1 superfamily includes 7 agonist proteins (including IL-1α and IL-1β), 3 receptor antagonists (including IL-1Ra) and the anti-inflammatory cytokine IL-37. xref IL-1α and IL-1β are distinct pro-inflammatory cytokines produced by multiple cell types, e.g., monocytes, macrophages, and neutrophils, as well as by cells in joint tissues e.g., synovial fibroblasts, chondrocytes and osteoclasts. xref They exert a wide range of biological and physiological effects throughout the body, including fever following stimulation in the central nervous system, innate resistance to infection, xref prostaglandin synthesis, xref T- and B-lymphocyte activation, IL-2 production, expression of cytokines, chemokines, nitric oxide synthetase, and matrix metalloproteinases (MMPs). xref IL-1α and IL-1β bind to the same receptor, namely the IL-1 receptor type I (IL-1R1) complexed to the IL-1 receptor accessory protein (IL-1RAcP) and induce similar physiological effects, including neutrophilia, fibroblast proliferation, cytotoxicity for certain cells, induction of collagenases, and increased production of colony stimulating factors and collagen. xref The effects of IL-1 are negatively regulated by 2 endogenous inhibitors, namely IL-1 receptor 2 (IL-1R2), which is related to the IL-1R1 and lacks a cytoplasmic domain, and IL-1 receptor antagonist IL-1Ra, which mimics the binding of IL-1β to IL-1R1 but fails to recruit the IL-1RAcP, preventing downstream signaling. xref "
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"Interestingly, a structural complex of the IL-1R1-ECD with a small antagonist peptide is available (PDB entry 1G0Y), showing a 170° rotation of D3 relative to a reference D3 in the IL-1R1:IL-1β complex (PDB entry 1ITB), and thus exposing an unexpected binding mode for the peptide [ xref ]."
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"Because mice deficient in the IL-1R cannot respond to IL-1, this result demonstrated that either IL-1a or IL-1b, both of which bind to the IL-1R, contributed to acute pathology after rVSV immunization.Mice immunized with VSV vaccine vectors produce IL-1b systemically and at the injection site Both IL-1a and IL-1b are regarded as pro-inflammatory cytokines, but IL-1b rather than IL-1a has been more commonly associated with symptoms such as weight loss and fever that are induced by infection with a live virus or other immune stimulus [16, 17] ."
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"Indeed studies with anakinra, a non glycosylated form of the endogenous antagonist of the IL-1 receptor, IL-1Ra, and rilonacept, which binds to IL-1beta with high affinity and thus blocks the binding of IL-1beta to its receptor, have demonstrated promising therapeutic activity in patients with CAPS [XREF_BIBR - XREF_BIBR]."
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"IL-1β binds to its receptor IL-1R and recruits myeloid differentiation primary response protein MyD88 and IL-1R–associated kinase 4 (Irak4) to phosphorylate Irak1, enabling transient recruitment of TNF receptor–associated factor 6, dissociation of Irak1 from the receptor, and activation of Tak1 ( xref )."
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"Meanwhile, binding of IL-1β with IL-1R on glia lineage cells recruits the AcP adaptor protein, which is predominantly expressed on astrocytes and microglia, and promotes NF-κB mediated transcription of other inflammatory cytokines such TNF-α ( xref ) and IL-6 ( xref ; xref ; xref ) suggesting that IL-1β plays an executive role in formation of neuroinflammatory responses."
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"Binding of IL-1β to IL-1R1 could directly stimulate myelopoiesis in a cell-intrinsic fashion, or alternatively induce a signaling cascade leading to the production of proliferative cytokines (e.g. G-CSF, M-CSF), which, in turn, act on other hematopoietic or non-hematopoietic cells (e.g., endothelial cells) in a cell-extrinsic fashion."
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"XREF_BIBR The effects of IL-1 are negatively regulated by 2 endogenous inhibitors, namely IL-1 receptor 2 (IL-1R2), which is related to the IL-1R1 and lacks a cytoplasmic domain, and IL-1 receptor antagonist IL-1Ra, which mimics the binding of IL-1beta to IL-1R1 but fails to recruit the IL-1RAcP, preventing downstream signaling."