Novel irreversible caspase-1 inhibitor attenuates the maturation of intracellular interleukin-1β

2007 ◽  
Vol 85 (1) ◽  
pp. 56-65 ◽  
Author(s):  
Xue-Qin Ma ◽  
Hua-Jie Zhang ◽  
Ya-Hui Zhang ◽  
Yi-Hua Chen ◽  
Fang Wu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Proinflammatory Cytokines ◽  
Caspase 3 ◽  
Inflammatory Diseases ◽  
Interleukin 1Β ◽  
Interleukin 18 ◽  
Caspase 1

. Caspase-1, the most efficient enzyme in processing the proinflammatory cytokines interleukin 1β and interleukin 18 in humans, is associated with inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and some neuronal diseases. We previously reported that isoquinoline-1,3,4-trione and its derivatives are novel caspase-3 inhibitors that could attenuate apoptosis in vitro and in vivo. Here we report a novel derivative of isoquinoline-1,3,4-trione that is highly potent in inhibiting caspase-1 activity in an irreversible and slow-binding manner, thus inhibiting cellular caspase-1 activity and the maturation of interleukin 1β in U-937 cells.

scholarly journals Carbon Monoxide Inhibits Tenascin-C Mediated Inflammation via IL-10 Expression in a Septic Mouse Model

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Md. Jamal Uddin ◽  
Chun-shi Li ◽  
Yeonsoo Joe ◽  
Yingqing Chen ◽  
Qinggao Zhang ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Proinflammatory Cytokines ◽  
Tissue Injury ◽  
Inflammatory Diseases ◽  
Septic Mouse ◽  
Induced Expression ◽  
Tenascin C ◽  
Co Gas

Tenascin-C (TN-C), an extracellular matrix (ECM) glycoprotein, is specifically induced upon tissue injury and infection and during septic conditions. Carbon monoxide (CO) gas is known to exert various anti-inflammatory effects in various inflammatory diseases. However, the mechanisms underlying the effect of CO on TN-C-mediated inflammation are unknown. In the present study, we found that treatment with LPS significantly enhanced TN-C expression in macrophages. CO gas, or treatment with the CO-donor compound, CORM-2, dramatically reduced LPS-induced expression of TN-C and proinflammatory cytokines while significantly increased the expression of IL-10. Treatment with TN-C siRNA significantly suppressed the effects of LPS on proinflammatory cytokines production. TN-C siRNA did not affect the CORM-2-dependent increase of IL-10 expression. In cells transfected with IL-10 siRNA, CORM-2 had no effect on the LPS-induced expression of TN-C and its downstream cytokines. These data suggest that IL-10 mediates the inhibitory effect of CO on TN-C and the downstream production of proinflammatory cytokines. Additionally, administration of CORM-2 dramatically reduced LPS-induced TN-C and proinflammatory cytokines production while expression of IL-10 was significantly increased. In conclusion, CO regulated IL-10 expression and thus inhibited TN-C-mediated inflammationin vitroandin vivo.

scholarly journals Salmonella-Induced Caspase-2 Activation in Macrophages

2000 ◽  
Vol 192 (7) ◽  
pp. 1035-1046 ◽  
Author(s):  
Veronika Jesenberger ◽  
Katarzyna J. Procyk ◽  
Junying Yuan ◽  
Siegfried Reipert ◽  
Manuela Baccarini
Keyword(s):  
Type Iii Secretion ◽  
Caspase 3 ◽  
Secretion System ◽  
Caspase 1 ◽  
Chemical Inhibition ◽  
Induction Of Apoptosis ◽  
Caspase 2 ◽  
Induced Apoptosis

The enterobacterial pathogen Salmonella induces phagocyte apoptosis in vitro and in vivo. These bacteria use a specialized type III secretion system to export a virulence factor, SipB, which directly activates the host's apoptotic machinery by targeting caspase-1. Caspase-1 is not involved in most apoptotic processes but plays a major role in cytokine maturation. We show that caspase-1–deficient macrophages undergo apoptosis within 4–6 h of infection with invasive bacteria. This process requires SipB, implying that this protein can initiate the apoptotic machinery by regulating components distinct from caspase-1. Invasive Salmonella typhimurium targets caspase-2 simultaneously with, but independently of, caspase-1. Besides caspase-2, the caspase-1–independent pathway involves the activation of caspase-3, -6, and -8 and the release of cytochrome c from mitochondria, none of which occurs during caspase-1–dependent apoptosis. By using caspase-2 knockout macrophages and chemical inhibition, we establish a role for caspase-2 in both caspase-1–dependent and –independent apoptosis. Particularly, activation of caspase-1 during fast Salmonella-induced apoptosis partially relies on caspase-2. The ability of Salmonella to induce caspase-1–independent macrophage apoptosis may play a role in situations in which activation of this protease is either prevented or uncoupled from the induction of apoptosis.

scholarly journals Inhibitory Effect ofChrysanthemum zawadskiiHerbich var.latilobumKitamura Extract on RANKL-Induced Osteoclast Differentiation

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Dong Ryun Gu ◽  
Jin-Ki Hwang ◽  
Munkhsoyol Erkhembaatar ◽  
Kang-Beom Kwon ◽  
Min Seuk Kim ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Diseases ◽  
Osteoclast Differentiation ◽  
Ethanol Extract ◽  
Inhibitory Effect ◽  
Bone Diseases ◽  
Dependent Manner ◽  
Erk Activation

Chrysanthemum zawadskii Herbichvar.latilobum Kitamura, known as “Gujulcho” in Korea, has been used in traditional medicine to treat various inflammatory diseases, including rheumatoid arthritis. However, these effects have not been tested on osteoclasts, the bone resorbing cells that regulate bone metabolism. Here, we investigated the effects ofC. zawadskiiHerbich var.latilobumKitamura ethanol extract (CZE) on osteoclast differentiation induced by treatment with the receptor activator of NF-κB ligand (RANKL). CZE inhibited osteoclast differentiation and formation in a dose-dependent manner. The inhibitory effect of CZE on osteoclastogenesis was due to the suppression of ERK activation and the ablation of RANKL-stimulated Ca2+-oscillation via the inactivation of PLCγ2, followed by the inhibition of CREB activation. These inhibitory effects of CZE resulted in a significant repression of c-Fos expression and a subsequent reduction of NFATc1, a key transcription factor for osteoclast differentiation, fusion, and activationin vitroandin vivo. These results indicate that CZE negatively regulates osteoclast differentiation and may be a therapeutic candidate for the treatment of various bone diseases, such as postmenopausal osteoporosis, rheumatoid arthritis, and periodontitis.

scholarly journals The E3 Ubiquitin Ligase TRIM65 Negatively Regulates Inflammasome Activation Through Promoting Ubiquitination of NLRP3

2021 ◽  
Vol 12 ◽  
Author(s):  
Tiantian Tang ◽  
Ping Li ◽  
Xinhui Zhou ◽  
Rui Wang ◽  
Xiuqin Fan ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Neutrophil Migration ◽  
Inflammasome Activation ◽  
Regulation Mechanism ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

The dysregulation of NLRP3 inflammasome plays a critical role in pathogenesis of various human inflammatory diseases, thus NLRP3 inflammasome activation must be tightly controlled at multiple levels. However, the underlying mechanism regulating NLRP3 inflammasome activation remains unclear. Herein, the effects of Tripartite motif-containing protein 65 (TRIM65) on NLRP3 inflammasome activation and the underlying molecular mechanism were investigated in vitro and in vivo. Inhibition or deletion of Trim65 could significantly strengthen agonist induced NLRP3 inflammasome activation in THP-1 cells and BMDMs, indicated by increased caspase-1 activation and interleukin-1β secretion. However, TRIM65 had no effect on poly (dA: dT)-induced AIM2 inflammasome activation or flagellin-induced IPAF inflammasome activation. Mechanistically, immunoprecipitation assays demonstrated that TRIM65 binds to NACHT domain of NLRP3, promotes lys48- and lys63- linked ubiquitination of NLRP3 and restrains the NEK7-NLRP3 interaction, thereby inhibiting NLRP3 inflammasome assembly, caspase-1 activation, and IL-1β secretion. In vivo, three models of inflammatory diseases were used to confirm the suppression role of TRIM65 in NLRP3 inflammasome activation. TRIM65-deficient mice had a higher production of IL-1β induced by lipopolysaccharide in sera, and more IL-1β secretion and neutrophil migration in the ascites, and more severity of joint swelling and associated IL-1β production induced by monosodium urate, suggesting that TRIM65 deficiency was susceptible to inflammation. Therefore, the data elucidate a TRIM65-dependent negative regulation mechanism of NLRP3 inflammasome activation and provide potential therapeutic strategies for the treatment of NLRP3 inflammasome-related diseases.

scholarly journals Inhibitory Effect of Methotrexate on Rheumatoid Arthritis Inflammation and Comprehensive Metabolomics Analysis Using Ultra-Performance Liquid Chromatography-Quadrupole Time of Flight-Mass Spectrometry (UPLC-Q/TOF-MS)

2018 ◽  
Vol 19 (10) ◽  
pp. 2894 ◽  
Author(s):  
Zhiqiang Pang ◽  
Guoqiang Wang ◽  
Nan Ran ◽  
Hongqiang Lin ◽  
Ziyan Wang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inhibitory Effect ◽  
Sphingolipid Metabolism ◽  
Enzyme Linked Immunosorbent Assay ◽  
Joint Tissue ◽  
Caspase 1 ◽  
Comprehensive Metabolomics ◽  
Metabolomics Analysis

Rheumatoid arthritis (RA) is a common autoimmune disease. The inflammation in joint tissue and system endanger the human health seriously. Methotrexate have exhibited a satisfactory therapeutic effect in clinical practice. The aim of this research was to establish the pharmacological mechanism of methotrexate on RA therapy. Collagen induced arthritic rats were used to identify how methotrexate alleviates inflammation in vivo. Lipopolysaccharide-induced inflammatory proliferation in macrophages was also be detected in vitro. The activation level of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Nucleotide binding domain and leucine-rich repeat pyrin 3 domain (NLRP3)/Caspase-1 and related cytokines were examined by real-time PCR and western blotting or quantified with the enzyme-linked immunosorbent assay. Comprehensive metabolomics analysis was performed to identify the alteration of metabolites. Results showed that treating with methotrexate could alleviate the inflammatory condition, downregulate the activation of NF-κB and NLRP3/Caspase-1 inflammatory pathways and reduce the level of related cytokines. Docking interaction between methotrexate and caspase-1 was visualized as six H-bonds indicating a potential inhibitory effect. Metabolomics analysis reported three perturbed metabolic inflammation related pathways including arachidonic acid, linoleic acid and sphingolipid metabolism. These findings indicated that methotrexate could inhibit the onset of inflammation in joint tissue by suppressing the activation of NF-κB and NLRP3/Caspase-1 pathways and regulating the inflammation related metabolic networks.

scholarly journals The ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Swarna L. Vijayaraj ◽  
Rebecca Feltham ◽  
Maryam Rashidi ◽  
Daniel Frank ◽  
Zhengyang Liu ◽  
...  
Keyword(s):  
Electrostatic Interaction ◽  
Inflammatory Diseases ◽  
Salt Bridge ◽  
Proteasomal Degradation ◽  
Interleukin 1Β ◽  
Collateral Damage ◽  
Caspase 1 ◽  
Microbial Responses

AbstractInterleukin-1β (IL-1β) is activated by inflammasome-associated caspase-1 in rare autoinflammatory conditions and in a variety of other inflammatory diseases. Therefore, IL-1β activity must be fine-tuned to enable anti-microbial responses whilst limiting collateral damage. Here, we show that precursor IL-1β is rapidly turned over by the proteasome and this correlates with its decoration by K11-linked, K63-linked and K48-linked ubiquitin chains. The ubiquitylation of IL-1β is not just a degradation signal triggered by inflammasome priming and activating stimuli, but also limits IL-1β cleavage by caspase-1. IL-1β K133 is modified by ubiquitin and forms a salt bridge with IL-1β D129. Loss of IL-1β K133 ubiquitylation, or disruption of the K133:D129 electrostatic interaction, stabilizes IL-1β. Accordingly, Il1bK133R/K133R mice have increased levels of precursor IL-1β upon inflammasome priming and increased production of bioactive IL-1β, both in vitro and in response to LPS injection. These findings identify mechanisms that can limit IL-1β activity and safeguard against damaging inflammation.

scholarly journals New horizons of methotrexate application

2020 ◽  
Vol 17 (1) ◽  
pp. 20-26
Author(s):  
Vladimir Maksimović ◽  
Svetlana Goločorbin-Kon ◽  
Momir Mikov ◽  
Jelena Cvejić ◽  
Zora Pavlović-Popović ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Bowel Disease ◽  
Anticancer Drug ◽  
Bowel Disease ◽  
Targeted Delivery ◽  
Inflammatory Diseases ◽  
New Horizons ◽  
Inflammatory Bowel

Methotrexate is an anti-inflammatory and anticancer drug that has been used in the treatment of various oncological and inflammatory diseases (such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, sarcoidosis, etc.). Scientists are working on finding optimal formulation that will maintain its efficacy and improve safety and nanoparticles have shown to be carriers with great potential as they protect the drug from degradation while at the same time they increase absorption. In vivo and in vitro studies of numerous nanoparticle preparations have showed that they generally have appropriate characteristics and can be carriers for targeted delivery of methotrexate to the tissues affected by disease. Topical preparations of methotrexate, mainly for the treatment of psoriasis, have also been assessed in various research and have showed promising results. Further research is warranted by the obtained results and will hopefully lead to new methotrexate formulations that will be approved by regulatory authorities and used instead of existing ones to improve efficacy of the drug and patients' safety.

scholarly journals Ligustrazine Alleviate Acute Lung Injury Through Suppressing Pyroptosis and Apoptosis of Alveolar Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Rundong Jiang ◽  
Jiaqi Xu ◽  
Yuezhong Zhang ◽  
Xuanmeng Zhu ◽  
Jiachen Liu ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Caspase 3 ◽  
Inflammatory Cells ◽  
Inflammatory Factors ◽  
Caspase 8 ◽  
Caspase 1 ◽  
Macrophages Polarization ◽  
M1 Type

Ligustrazine (Tetramethylpyrazine, TMP) is an active substance extracted from the Umbelliferae plant Ligusticum chuanxiong. It has been proven to have antioxidant and inflammation effects. The study was designed to explore the efficacy and specific mechanism of TMP for ALI/ARDS treatment. Here, we confirmed that TMP decreased the infiltration of inflammatory cells in alveoli and the secretion of pro-inflammatory factors, which is comparable to glucocorticoids in vivo. In vitro, TMP inhibited the polarization of M1-type macrophages, and to a certain extent, promoted M2-type repolarization, thus reducing LPS-induced massive transcription and secretion of IL-1β, IL-18, TNF-ɑ and other inflammatory factors. Besides, TMP reduced expression of NLRP3, inhibited the formation of inflammasome complexes, and decreased the cleavage of caspase-1, leading to reduced cell pyroptosis and accompanying inflammation. TMP also inhibited apoptosis through caspase-8/caspase-3 signaling pathways. Our study indicates that TMP improved ALI through inhibiting the TLR4/TRAF6/NFκB/NLRP3/caspase-1 and TLR4/caspase-8/caspase-3 signaling pathways, which reversed macrophages polarization, reduced cell pyroptosis and apoptosis, which provides a theoretical basis of using TMP in treating ALI in the future.

scholarly journals Neutrophils Facilitate Prolonged Inflammasome Response in the DAMP-Rich Inflammatory Milieu

2021 ◽  
Vol 12 ◽  
Author(s):  
Seunghwan Son ◽  
Sung-Hyun Yoon ◽  
Byeong Jun Chae ◽  
Inhwa Hwang ◽  
Do-Wan Shim ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Macrophage Polarization ◽  
Interleukin 1Β ◽  
Inflammasome Activation ◽  
M2 Macrophage ◽  
Mitochondrial Depolarization ◽  
Activated Neutrophils

Aberrant inflammasome activation contributes to various chronic inflammatory diseases; however, pyroptosis of inflammasome-active cells promptly terminates local inflammasome response. Molecular mechanisms underlying prolonged inflammasome signaling thus require further elucidation. Here, we report that neutrophil-specific resistance to pyroptosis and NLRP3 desensitization can facilitate sustained inflammasome response and interleukin-1β secretion. Unlike macrophages, inflammasome-activated neutrophils did not undergo pyroptosis, indicated by using in vitro cell-based assay and in vivo mouse model. Intriguingly, danger-associated molecular patterns (DAMP)-rich milieu in the inflammatory region significantly abrogated NLRP3-activating potential of macrophages, but not of neutrophils. This macrophage-specific NLRP3 desensitization was associated with DAMP-induced mitochondrial depolarization that was not observed in neutrophils due to a lack of SARM1 expression. Indeed, valinomycin-induced compulsory mitochondrial depolarization in neutrophils restored inflammasome-dependent cell death and ATP-induced NLRP3 desensitization in neutrophils. Alongside prolonged inflammasome-activating potential, neutrophils predominantly secreted interleukin-1β rather than other proinflammatory cytokines upon NLRP3 stimulation. Furthermore, inflammasome-activated neutrophils did not trigger efferocytosis-mediated M2 macrophage polarization essential for the initiation of inflammation resolution. Taken together, our results indicate that neutrophils can prolong inflammasome response via mitochondria-dependent resistance to NLRP3 desensitization and function as major interleukin-1β-secreting cells in DAMP-rich inflammatory region.

scholarly journals Synthetic 4-Hydroxy Auxarconjugatin B, a Novel Autophagy Inducer, Attenuates Gouty Inflammation by Inhibiting the NLRP3 Inflammasome

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 279 ◽  
Author(s):  
Chih-Yu Hsieh ◽  
Lan-Hui Li ◽  
Yulin Lam ◽  
Zhanxiong Fang ◽  
Chin Heng Gan ◽  
...  
Keyword(s):  
Uric Acid ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Gouty Arthritis ◽  
Mechanistic Study ◽  
Caspase 1 ◽  
Autophagy Induction ◽  
Active Caspase

Gouty arthritis results from the generation of uric acid crystals within the joints. These uric acid crystals activate the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, which is involved in chronic inflammatory diseases, including gouty arthritis. This study identified the polyenylpyrrole derivative 4-hydroxy auxarconjugatin B (4-HAB), a novel autophagy inducer, which attenuated uric acid crystals-mediated activation of the NLRP3 inflammasome in vitro and in vivo. 4-HAB dose-dependently reduced the release of interleukin (IL)-1β, IL-18, active caspase-1 and apoptosis-associated speck-like protein (ASC) in uric acid crystals-activated macrophages. In a mechanistic study, 4-HAB was shown to inhibit uric acid crystals-induced mitochondrial damage, lysosomal rupture and ASC oligomerization. Additionally, 4-HAB inhibited the NLRP3 inflammasome through Sirt1-dependent autophagy induction. Furthermore, the anti-inflammatory properties of 4-HAB were confirmed in a mouse model of uric acid crystals-mediated peritonitis by the reduced levels of neutrophil influx, IL-1β, active caspase-1, IL-6 and MCP-1 in lavage fluids. In conclusion, 4-HAB attenuates gouty inflammation, in part by attenuating activation of the NLRP3 inflammasome through the Sirt1/autophagy induction pathway.

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