Background and Aims:Hepatic fibrosis(HF)is a critical step in the progression of hepatocellular carcinoma(HCC).Gene associated with retinoid-IFN-induced mortality 19(GRIM19),an essential component of mitochondrial res...Background and Aims:Hepatic fibrosis(HF)is a critical step in the progression of hepatocellular carcinoma(HCC).Gene associated with retinoid-IFN-induced mortality 19(GRIM19),an essential component of mitochondrial respiratory chain complex I,is frequently attenuated in various human cancers,including HCC.Here,we aimed to investigate the potential relationship and underlying mechanism between GRIM19 loss and HF pathogenesis.Methods:GRIM19 expression was evaluated in normal liver tissues,hepatitis,hepatic cirrhosis,and HCC using human liver disease spectrum tissue microarrays.We studied hepatocyte-specific GRIM19 knockout mice and clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein-9(Cas9)lentivirus-mediated GRIM19 gene-editing in murine hepatocyte AML12 cells in vitro and in vivo.We performed flow cytometry,immunofluorescence,immunohistochemistry,western blotting,and pharmacological intervention to uncover the potential mechanisms underlying GRIM19 loss-induced HF.Results:Mitochondrial GRIM19 was progressively downregulated in chronic liver disease tissues,including hepatitis,cirrhosis,and HCC tissues.Hepatocyte-specific GRIM19 heterozygous deletion induced spontaneous hepatitis and subsequent liver fibrogenesis in mice.In addition,GRIM19 loss caused chronic liver injury through reactive oxygen species(ROS)-mediated oxidative stress,resulting in aberrant NF-κB activation via an IKK/IKB partner in hepatocytes.Further-more,GRIM19 loss activated NLRP3-mediated IL33 signaling administration of the NLRP3 inhibitor MCC950 dramatically via the ROS/NF-κB pathway in hepatocytes.Intraperitoneal alleviated GRIM19 loss-driven HF in vivo.Conclusions:The mitochondrial GRIM19 loss facilitates liver fibrosis through NLRP3/IL33 activation via ROS/NF-κB signaling,providing potential therapeutic approaches for earlier HF prevention.展开更多
目的研究不同刺激条件对人角质形成细胞Ha Ca T细胞中TSLP、IL-33表达水平的影响,探讨过敏性疾病中关键启动因子TSLP、IL-33体外表达细胞模型的最佳刺激方法。方法应用角质形成细胞无血清培养液(K-SFM)体外培养Ha Ca T细胞,给予不同刺激...目的研究不同刺激条件对人角质形成细胞Ha Ca T细胞中TSLP、IL-33表达水平的影响,探讨过敏性疾病中关键启动因子TSLP、IL-33体外表达细胞模型的最佳刺激方法。方法应用角质形成细胞无血清培养液(K-SFM)体外培养Ha Ca T细胞,给予不同刺激剂,筛选出明显促进Ha Ca T细胞中TSLP和IL-33表达的刺激剂。进而考察单独与联合刺激剂时的量效关系,最后对选出的刺激剂进行时效关系考察。TSLP和IL-33表达水平采用ELISA和免疫荧光法检测。结果 (1)Poly(I:C)与TNF-α两种刺激剂单独使用时均能明显刺激Ha Ca T细胞分泌TSLP和IL-33,其余刺激剂在本实验浓度范围内未见明显差异。(2)Poly(I:C)100 mg·L-1与TNF-α20μg·L-1联合刺激对Ha Ca T细胞表达TSLP和IL-33的促进作用最为明显。(3)对Poly(I:C)100 mg·L-1与TNF-α20μg·L-1联合刺激Ha Ca T细胞的时效关系考察发现,刺激12 h Ha Ca T细胞中TSLP和IL-33的表达水平最高。结论不同刺激剂和刺激时间对体外刺激Ha Ca T细胞表达细胞因子TSLP和IL-33的效应不同,其中以Poly(I:C)100 mg·L-1与TNF-α20μg·L-1联合刺激Ha Ca T细胞12 h后,TSLP和IL-33的表达水平升高最为明显。该结果为过敏性疾病的病理机制及药物作用研究提供了合适的方法。展开更多
AIM:To explore the association of single nucleotide polymorphisms(SNPs)in the IL33/IL1RL1 gene region with the susceptibility to Behcet’s disease(BD)in a Chinese Han population.METHODS:A total of eight SNPs in the ca...AIM:To explore the association of single nucleotide polymorphisms(SNPs)in the IL33/IL1RL1 gene region with the susceptibility to Behcet’s disease(BD)in a Chinese Han population.METHODS:A total of eight SNPs in the candidate gene region(rs11792633,rs7025417,rs10975519 and rs1048274 in IL33;rs2310220,rs12712142,rs13424006 and rs3821204 in IL1RL1)were genotyped in783 BD patients and 701 healthy controls by the Sequenom Mass Array i PLEX platform.RESULTS:A statistically significant association was observed between IL1RL1 rs12712142 and BD patients.The frequency of IL1RL1 rs12712142 variant allele A was significantly lower in BD patients than that in controls(OR=0.8,95%CI:0.69-0.94,Pc=0.039);the genotype distribution(Pc=0.043)and additive and dominant genetic model analyses(OR=0.8,95%CI:0.69-0.94,Pc=0.040 and OR=0.72,95%CI:0.58-0.88,Pc=0.011)also indicated a strong association between rs12712142 and BD patients.CONCLUSION:This is the first study to reveal the association between IL1RL1 rs12712142 variant allele A and the decreased risk of BD in the Chinese Han population,indicating a protective role of IL1RL1 in the pathogenesis of BD.展开更多
基金partially supported by the National Nature Science Foundation of China[No.32171119,No.32371173]the general basic research project from the Ministry of Education Key Laboratory of Child Development and Disorders[GBRP-202116]+2 种基金the Nature Science Foundation of Chongqing Science and Technology Bureau[CSTB2022NSCQ-MSX0838]the Science and Technology Research Program of Chongqing Municipal Education Commission[KJZD-K202100401]the Future Medical Youth Innovation Team Support Project of Chongqing Medical University[W0175].
文摘Background and Aims:Hepatic fibrosis(HF)is a critical step in the progression of hepatocellular carcinoma(HCC).Gene associated with retinoid-IFN-induced mortality 19(GRIM19),an essential component of mitochondrial respiratory chain complex I,is frequently attenuated in various human cancers,including HCC.Here,we aimed to investigate the potential relationship and underlying mechanism between GRIM19 loss and HF pathogenesis.Methods:GRIM19 expression was evaluated in normal liver tissues,hepatitis,hepatic cirrhosis,and HCC using human liver disease spectrum tissue microarrays.We studied hepatocyte-specific GRIM19 knockout mice and clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein-9(Cas9)lentivirus-mediated GRIM19 gene-editing in murine hepatocyte AML12 cells in vitro and in vivo.We performed flow cytometry,immunofluorescence,immunohistochemistry,western blotting,and pharmacological intervention to uncover the potential mechanisms underlying GRIM19 loss-induced HF.Results:Mitochondrial GRIM19 was progressively downregulated in chronic liver disease tissues,including hepatitis,cirrhosis,and HCC tissues.Hepatocyte-specific GRIM19 heterozygous deletion induced spontaneous hepatitis and subsequent liver fibrogenesis in mice.In addition,GRIM19 loss caused chronic liver injury through reactive oxygen species(ROS)-mediated oxidative stress,resulting in aberrant NF-κB activation via an IKK/IKB partner in hepatocytes.Further-more,GRIM19 loss activated NLRP3-mediated IL33 signaling administration of the NLRP3 inhibitor MCC950 dramatically via the ROS/NF-κB pathway in hepatocytes.Intraperitoneal alleviated GRIM19 loss-driven HF in vivo.Conclusions:The mitochondrial GRIM19 loss facilitates liver fibrosis through NLRP3/IL33 activation via ROS/NF-κB signaling,providing potential therapeutic approaches for earlier HF prevention.
文摘目的研究不同刺激条件对人角质形成细胞Ha Ca T细胞中TSLP、IL-33表达水平的影响,探讨过敏性疾病中关键启动因子TSLP、IL-33体外表达细胞模型的最佳刺激方法。方法应用角质形成细胞无血清培养液(K-SFM)体外培养Ha Ca T细胞,给予不同刺激剂,筛选出明显促进Ha Ca T细胞中TSLP和IL-33表达的刺激剂。进而考察单独与联合刺激剂时的量效关系,最后对选出的刺激剂进行时效关系考察。TSLP和IL-33表达水平采用ELISA和免疫荧光法检测。结果 (1)Poly(I:C)与TNF-α两种刺激剂单独使用时均能明显刺激Ha Ca T细胞分泌TSLP和IL-33,其余刺激剂在本实验浓度范围内未见明显差异。(2)Poly(I:C)100 mg·L-1与TNF-α20μg·L-1联合刺激对Ha Ca T细胞表达TSLP和IL-33的促进作用最为明显。(3)对Poly(I:C)100 mg·L-1与TNF-α20μg·L-1联合刺激Ha Ca T细胞的时效关系考察发现,刺激12 h Ha Ca T细胞中TSLP和IL-33的表达水平最高。结论不同刺激剂和刺激时间对体外刺激Ha Ca T细胞表达细胞因子TSLP和IL-33的效应不同,其中以Poly(I:C)100 mg·L-1与TNF-α20μg·L-1联合刺激Ha Ca T细胞12 h后,TSLP和IL-33的表达水平升高最为明显。该结果为过敏性疾病的病理机制及药物作用研究提供了合适的方法。
基金the National Natural Science Foundation of China (No.81770917)。
文摘AIM:To explore the association of single nucleotide polymorphisms(SNPs)in the IL33/IL1RL1 gene region with the susceptibility to Behcet’s disease(BD)in a Chinese Han population.METHODS:A total of eight SNPs in the candidate gene region(rs11792633,rs7025417,rs10975519 and rs1048274 in IL33;rs2310220,rs12712142,rs13424006 and rs3821204 in IL1RL1)were genotyped in783 BD patients and 701 healthy controls by the Sequenom Mass Array i PLEX platform.RESULTS:A statistically significant association was observed between IL1RL1 rs12712142 and BD patients.The frequency of IL1RL1 rs12712142 variant allele A was significantly lower in BD patients than that in controls(OR=0.8,95%CI:0.69-0.94,Pc=0.039);the genotype distribution(Pc=0.043)and additive and dominant genetic model analyses(OR=0.8,95%CI:0.69-0.94,Pc=0.040 and OR=0.72,95%CI:0.58-0.88,Pc=0.011)also indicated a strong association between rs12712142 and BD patients.CONCLUSION:This is the first study to reveal the association between IL1RL1 rs12712142 variant allele A and the decreased risk of BD in the Chinese Han population,indicating a protective role of IL1RL1 in the pathogenesis of BD.
