更新于：2024-11-01

IL1R1 x TNFR

更新于：2024-11-01

基本信息

关联

项与 IL1R1 x TNFR 相关的药物

99mTc TR-21

靶点

IL1R1 x TNFR

作用机制

IL1R1拮抗剂 [+1]

在研机构-

原研机构

Avid Radiopharmaceuticals, Inc.

在研适应症-

非在研适应症

炎症

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 IL1R1 x TNFR 相关的临床结果

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100 项与 IL1R1 x TNFR 相关的转化医学

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0 项与 IL1R1 x TNFR 相关的专利（医药）

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项与 IL1R1 x TNFR 相关的文献（医药）

2023-10-01·Toxicology

Exploring cardiac impact of oral nicotine exposure in a transplantable Neoplasm Mice Model: Insights from biochemical analysis, morphometry, and molecular docking: Chlorella vulgaris green algae support

Article

作者: Moustafa, Gihan G ; Mohamed, Amany Abdel-Rahman ; El Bohy, Khlood M ; Alosaimi, Manal ; El Desoukey Mohammed, Heba ; Alqahtani, Leena S ; Metwally, Mohamed M M ; Abuzahrah, Samah S ; Alotaibi, Badriyah S ; Saber, Taghred M ; El-Far, Ali H

Nicotine-induced cardiac tissue damage is a concern for cancer patients, but the exact pathogenesis from nicotine oral exposure is unclear. This study was designed to investigate the impact of nicotine and Chlorella vulgaris (Ch. V) on cardiac glutathione homeostasis, inflammatory response, cardiac damage markers, apoptotic proteins and histopathological findings in an experimentally transplantable neoplasm mouse model (Ehrlich ascites carcinoma; EAC). In the in-vivo experiment, the female Swiss mice were divided into four groups: control, Ch.V (100 mg/kg), Nicotine (100 µg/ml/kg), and a combination group ( Nocotine+ Ch.V) for 40 days. Furthermore, in this study,the effects of C. vulgaris components on caspase-3, TNF-α, and IL-1β activity were explored using Molecular Operating Environment (MOE) docking software to ensure its ability to counteract the toxic effects of nicotine. The results indicated that nicotine has induced significant (P < 0.001) cardiopathic alterations in EAC-bearing mice with changes in cardiac tissue enzymes. C. Vulgaris attenuated the nicotine-induced cardiac glutathione inhibition, suppressed the inflammatory response, exerted antiapoptotic effects, mitigated myocardial injury biomarkers, and repaired cellular and tissue damage. Moreover, the molecular docking results revealed the ability of C. vulgaris to bind with interleukin-1 receptor type 1 (IL1R1) and tumor necrosis factor receptor superfamily member 1 A (TNFRSF1A) in the mice tissues, ameliorating apoptosis and inflammatory processes associated with nicotine-induced cardiotoxicity. This study provides a model for understanding nicotine-induced myocardial injury during experimentally transplantable neoplasm. It highlights C. vulgaris as a beneficial food supplement for cancer patients exposed to nicotine orally.

2023-09-01·Fish & Shellfish Immunology

A novel tumor necrosis factor receptor-associated factor 6 (TRAF6) gene from Macrobrachium rosenbergii involved in antibacterial defense against Aeromonas hydrophila

Article

作者: Longyant, Siwaporn ; Chaivisuthangkura, Parin ; Pasookhush, Phongthana ; Choolert, Chanitcha ; Vaniksampanna, Akapon

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an adapter protein that triggers downstream cascades mediated by both TNFR and the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily. TRAF6 is involved in various biological processes, including innate and adaptive immunity. In the present study, a homolog of TRAF6 from Macrobrachium rosenbergii (MrTRAF6) was identified and characterized. The full-length cDNA of MrTRAF6 consisted of 2,114 nucleotides with an open reading frame (ORF) of 1,695 nucleotides encoding a 564-amino acid protein that contained a conserved TRAF family motif including two RING-type zinc fingers and a C-terminal meprin and TRAF homology (MATH) domain. The putative amino sequence of MrTRAF6 shared 45.5-97.3% identity with TRAF6s from other crustacean species with the highest identity to Macrobrachium nipponense TRAF6. Phylogenetic analysis revealed that MrTRAF6 was closely related to TRAF6 of invertebrates and clustered with crustaceans. According to gene expression analysis, the MrTRAF6 transcript demonstrated broad expression in all tissues tested, with the highest expression level in gill and the lowest in muscle tissues. Upon immune challenge with Aeromonas hydrophila, significant upregulation of MrTRAF6 expression was found in the gill, hepatopancreas, hemocyte, and muscle. Furthermore, an RNA interference assay showed that silencing MrTRAF6 by dsRNA could reduce the expression of mannose-binding lectin (MBL) and crustin, but no significant change was detected in anti-lipopolysaccharide factor 5 (ALF5) levels. In addition, the cumulative mortality rate of MrTRAF6-silenced M. rosenbergii was significantly increased after A. hydrophila infection. These findings indicated that MrTRAF6 is involved in antibacterial activity and plays a critical role in the innate immune response of M. rosenbergii.

2023-03-01·Cell Reports

NF-κB activation enhances STING signaling by altering microtubule-mediated STING trafficking

Article

作者: Zhang, Lulu ; Yin, Hang ; Hou, Yanfei ; Su, Huili ; Wei, Xubiao ; Koci, Matthew D ; Wang, Zhimeng ; Liu, Peiyuan ; Zhang, Conggang ; Xu, Yifang

It is widely known that stimulator of interferon genes (STING) can trigger nuclear factor κB (NF-κB) signaling. However, whether and how the NF-κB pathway affects STING signaling remains largely unclear. Here, we report that Toll-like receptor (TLR)-, interleukin-1 receptor (IL-1R)-, tumor necrosis factor receptor (TNFR)-, growth factor receptor (GF-R)-, and protein kinase C (PKC)-mediated NF-κB signaling activation dramatically enhances STING-mediated immune responses. Mechanistically, we find that STING interacts with microtubules, which plays a crucial role in STING intracellular trafficking. We further uncover that activation of the canonical NF-κB pathway induces microtubule depolymerization, which inhibits STING trafficking to lysosomes for degradation. This leads to increased levels of activated STING that persist for a longer period of time. The synergy between NF-κB and STING triggers a cascade-amplified interferon response and robust host antiviral defense. In addition, we observe that several gain-of-function mutations of STING abolish the microtubule-STING interaction and cause abnormal STING trafficking and ligand-independent STING autoactivation. Collectively, our data demonstrate that NF-κB activation enhances STING signaling by regulating microtubule-mediated STING trafficking.

项与 IL1R1 x TNFR 相关的新闻（医药）

2023-01-27

·佰傲谷BioValley

单核细胞稳态

单核细胞是巨噬细胞和树突状细胞(monocyte-derived dendritic cells, MoDCs）的祖细胞，但它们也作为对环境变化和疾病作出反应的循环传感器。经典和非经典单核细胞在小鼠和人类中有两种主要的单核细胞群体，被称为经典和非经典群体，由特定的标记物定义，以及经典和非经典单核细胞之间的中间过渡群体。在稳态中，单核细胞监视血管系统或被招募来不断补充组织驻留的巨噬细胞（TRMs），例如在肠道中。在应对炎症、感染或组织损伤时，免疫细胞招募导致效应巨噬细胞的发展，排斥病原体和介导组织修复以及向树突状细胞分化(MoDCs）。一般意识上，经典表型单核细胞被认为是巨噬细胞或树突状细胞生成“管道”，哺乳动物宿主防御有益。单核细胞群的频率、活性和命运也与许多疾病有关，包括自身免疫、慢性炎症、心血管疾病和癌症。这些疾病中，作用于骨骼、血液和组织中的环境因素，会动态地改变单核细胞的转录景观，从而导致可增强疾病严重程度的表型（非经典表型），稳态打破。Trends Immunol. 2021内稳态中单核细胞的转录印迹TRM主要来源于胚胎来源，并能够进行长期的自我更新。在包括肠道、皮肤和心脏在内的一些组织中，经典单核细胞可以贡献TRM的一部分稳态库，并且在某些情况下可以完全取代它们。因此，在许多组织中（例如，脑巨噬细胞，小胶质细胞）都是来自两个胚胎来源的产物。在这种情况下，转录印记可以驱动组织表型。在小鼠中，对肠道的详细解剖表明，被招募的经典单核细胞中的TGFβR信号通过诱导多个肠道巨噬细胞特异性基因的表达，对单核细胞向肠巨噬细胞的最终分化是必不可少的。值得注意的是，与其他TRM相比，肠道巨噬细胞高表达RUNX3，这是TGF-β信号通路的中介物。其他报道的驱动肠道巨噬细胞表型的因素包括IL-10、芳基烃受体配体、微生物群副产物，以及对外源配体的低反应性状态。Trends Immunol. 2021生态位特异性信号诱导谱系决定转录因子（lineage-determining transcription factors，LDTFs）的表达，这些转录因子与核心巨噬细胞LDTFs协同作用，驱动新的增强子的选择。预先存在的和新的增强子进一步受到广泛表达的信号依赖转录因子（TFs）的作用的影响，它介导了内部和外部信号的影响。Immunity 2019荷兰根特大学（Ghent University）在Immunity发表研究成果，利用条件清除肝枯否细胞，追踪了单核细胞分化为枯否细胞的发育阶段。枯否细胞丢失诱导TNFR和IL-1R依赖的星状细胞和内皮细胞激活能力，导致趋化因子和粘附分子的短暂产生，影响单核细胞植入。植入的循环单核细胞转移到窦周空间，获得了DNA3的肝脏相关转录因子抑制因子（liver-associated transcription factors inhibitor of DNA 3，ID3）和肝脏X受体-a（liver X receptor-a，LXR-a）。与肝细胞的协同相互作用诱导了ID3的表达，而内皮细胞和星状细胞通过协同的NOTCH-BMP途径诱导了LXR-a。本研究表明，枯否细胞生态位由星状细胞、肝细胞和内皮细胞组成，它们共同形成了肝脏特异性巨噬细胞的特性。参考资料Bonnardel, J. et al. (2019) Stellate cells, hepatocytes, and endothelial cells imprint the Kupffer cell identity on monocytes colonizing the liver macrophage niche. Immunity 51, 638–654Robinson A, et al.Monocyte Regulation in Homeostasis and Malignancy，Trends Immunol. 2021 Feb;42(2):104-119.近期热门视频更多精彩视频，尽在佰傲谷视频号，欢迎关注~本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀‍ 点亮在看，传递信息♥

2022-12-21

·生物制药小编

炎症性衰老（Inflammageing）

炎症性衰老（Inflammageing）是一种无菌、低级别慢性炎症，随着年龄的增长而逐渐增强。不仅仅是年老的标志，还可导致健康衰退、身体虚弱、和老化相关疾病。Clin Rev Allergy Immunol . 2022 “垃圾累积理论”炎症性衰老潜在原因仍不清楚，有一些假设的模型，如细胞碎片累积，也被称为“垃圾衰老garb-aging”理论，随着年龄增加，细胞内的大分子会受损。当再加上修复和自噬的进行性衰退，这种积累的大分子损伤会导致细胞“垃圾”水平的增加，通过先天免疫信号引发炎症。这一理论与随后确定的衰老特征完全一致，包括蛋白质内稳态丧失、基因组的不稳定（包括修复能力的下降）和细胞信号传导改变。虽然垃圾积累可能在局部和全身炎症中发挥重要作用，但它不太可能是炎症的唯一驱动因素。炎症因子的复杂作用在大多数人群中，慢性无菌性炎症（炎症性衰老）随着实际年龄的增加而增加。整体炎症状态不仅与个体炎症标记物增加相关，还与各种炎症介质之间复杂的相互作用相关。1. 促炎标志物升高循环系统炎症因子随着年龄的增长而增加，包括IL-6、IL-8、IL-15、可溶性糖蛋白130（SGP130，参与IL-6信号传导）、sCD30 和MCP-1等。在用于评估炎症的常见临床血清生物标志物中，CRP和IL-6是迄今为止促炎因子中研究最集中的。它们与衰老（特别是IL-6）、不良的身体表现和死亡率密切相关，且IL-6可以诱导急性期蛋白如CRP的产生。IL-6是一种影响老年人大脑、骨骼和骨骼肌的“老年因子”。IL-6可通过血脑屏障（BBB），也可由神经细胞释放改变神经微环境，对神经发生和神经元产生不利影响。在骨组织中，IL-6可以影响成骨细胞和破骨细胞之间的平衡，与骨质疏松症和溶骨性疾病有关。在骨骼肌中，IL-6水平的解除可以发挥分解代谢作用，改变局部氧化还原平衡。IL-6也可通过SASP诱导进一步的炎症信号；因此，局部高水平的促炎细胞因子具有自我增强的能力。Ageing Research Reviews 80 (2022) 101697纤溶酶原激活抑制剂-1（PAI-1，也称为SERPIN1）与IL-6和CRP属于同一促炎因子簇，PAI-1的水平与其他衰老特征相关，包括步行速度下降和握力降低，是身体虚弱的标志。2. 抗炎细胞因子抗炎因子，就其本质而言，有望减少包括炎症性衰老在内的炎症。强的抗炎细胞因子IL-37确实如此，它在抑制有害炎症方面有明确的作用。表达人类IL-37的转基因小鼠，衰老相关促炎细胞因子很少增加，并随着年龄的增长维持B细胞祖细胞功能，恢复T细胞功能，改善血管、代谢和运动功能。同样，抗炎细胞因子IL-10的水平与年龄增长呈负相关，IL-10与高密度脂蛋白胆固醇一起被纳入抗炎集群，并与急性冠状动脉综合征患者的良好预后相关。与直觉相反，许多被归类为抗炎的因子随着年龄增加，但与生理功能不良相关。例如，可溶性TNF受体I（sTNFR-I）和II通过阻止TNF-α与膜TNFR的相互作用，作为TNF-α促炎信号传导的抑制剂。因此，它们将被预期是抗炎因子，它们与年龄的增长有很强的正相关，并与身体状况不良相关。白细胞介素-1受体拮抗剂（IL-1RA）可阻断IL-1信号传导，起抗炎作用。然而，IL-1RA水平与年龄呈正相关，并与IL-6和CRP属同一聚类，是独立于炎症暴露或基因型的老年人死亡率的一个重要预测因子。另外两种可溶性白细胞介素受体，IL-2可溶性受体（IL-2sR）和IL-6sR，与TNF-α和sTNFRs属于同一聚类，并与较差的身体机能相关。多种抗炎因子与年龄相关疾病之间的联系并不一定意味着这些分子是有害的，并导致炎症。相反，它们的升高可能反映了对促炎刺激的适应性生理反应，试图抑制炎症。如果高水平的抗炎因子与不良结果相关，则可能是适应性反应未能将炎症降低到一个破坏性阈值以下。3. 促炎/抗炎双重细胞因子IL-18、TNF-α等可以表现出抗炎和促炎双重作用，其中IL-18随着年龄增加而增加，是5年和10年死亡的独立危险预测因子。Cells 2022炎症性衰老与免疫衰老炎症性衰老产生于许多组织的免疫细胞衰老（immunosenescence）增加，以及骨髓生态位和个体先天和适应性免疫细胞的衰老相关变化，这共同导致了不适当的高水平的无菌性炎症，以及许多分泌性炎症因子，这些是炎症性衰老标志。Cells 2022总的来说，免疫衰老与炎症性衰老有着错综复杂的联系，通过先天免疫系统和适应性免疫系统的所有组分之间的相互作用，以及通过全身衰老细胞的SASP产生的炎症贡献。因此，在衰老的背景下，适应性免疫细胞通过增加自身免疫导致炎症，促炎Th17活动，和去除衰老细胞免疫监测的失败，而先天免疫细胞驱动炎症性衰老是通过骨髓倾斜，增加促炎症亚群，产生促炎反应。衰老的巨噬细胞可能无法从组织中清除分泌SASP的衰老细胞，因此先天免疫细胞的衰老可以直接或间接地促进炎症。简评：随着人体老化，产生炎症性衰老。通过体育锻炼（降低慢性炎症），饮食（地中海饮食，富含植物性食物等）等可以起到一定作用。一些相应的医药开发也在进行中，期待有好的临床结果。参考资料Augusto Bleve et al, Immunosenescence, Inflammaging, and Frailty: Role of Myeloid Cells in Age‑Related Diseases.Clin Rev Allergy Immunol . 2022 Jan 15;1-22. Varadhan, R.; Yao, W.; Matteini, A.; Beamer, B.A.; Xue, Q.-L.; Yang, H.; Manwani, B.; Reiner, A.; Jenny, N.; Parekh, N.; et al. Simple Biologically Informed Inflammatory Index of Two Serum Cytokines Predicts 10 Year All-Cause Mortality in Older Adults. J. Gerontol. A Biol. Sci. Med. Sci. 2014, 69, 165–173.Teissier, T.; Boulanger, E.; Cox, L.S. Interconnections between Inflammageing and Immunosenescence during Ageing. Cells 2022, 11, 359

临床研究