The innate immune responses,including inflammasome activation,are paramount for host defense against pathogen infection.In contrast to canonical and noncanonical inflammasome activation,in this study,heat-killed gram-...The innate immune responses,including inflammasome activation,are paramount for host defense against pathogen infection.In contrast to canonical and noncanonical inflammasome activation,in this study,heat-killed gram-negative bacteria(HK bacteria)were identified as single-step stimulators of the NLRP3 inflammasome in human monocytes,and they caused a moderate amount of IL-1βto be released from cells.Time course experiments showed that this alternative inflammasome response was finished within a few hours.Further analysis showed that the intrinsically limited NLRP3 inflammasome activation response was due to the negative regulation of caspase-8 by the short isoform of cFLIP(cFLIPs),which was activated by NF-κB.In contrast,overexpressed cFLIPS,but not overexpressed cFLIPL,inhibited the activation of caspase-8 and the release of IL-1βin response to HK bacteria infection in human monocytes.Furthermore,we demonstrated that TAK1 activity mediated the expression of cFLIPs and was upstream and essential for the caspase-8 cleavage induced by HK bacteria in human monocytes.The functional specificity of cFLIPs and TAK1 revealed unique responses of human monocytes to a noninvasive pathogen,providing novel insights into an alternative regulatory pathway of NLRP3 inflammasome activation.展开更多
目的:检测 cFIP_(short/long)在结肠肿瘤和癌旁组织的表达状况及其与p53基因突变的关系,初步探讨cFLIp在结肠肿瘤发生发展中的意义及p53对其调控作用。 方法:采用免疫组织化学法检测cnLIP在45例结肠腺癌、癌旁组织和42例结肠腺瘤组织中...目的:检测 cFIP_(short/long)在结肠肿瘤和癌旁组织的表达状况及其与p53基因突变的关系,初步探讨cFLIp在结肠肿瘤发生发展中的意义及p53对其调控作用。 方法:采用免疫组织化学法检测cnLIP在45例结肠腺癌、癌旁组织和42例结肠腺瘤组织中的表达,同时对以上45例结肠腺癌组织行免疫组化染色检测突变p53的表达状况。 cFLIP_(short/long)在结肠腺癌、癌旁组织和腺瘤中的表达差异采用多个样本两两比较的秩和检验(Nemenyi法),cFLIP_(short/long)和突变p53的表达关系采用t检验分析。 结果:cFLIP_(short/long)在结肠腺癌、癌旁组织和腺瘤中都有阳性表达,其染色记分均数分别为3.28±0.37、1.25±0.64和1.13±0.64。结肠腺癌组织的表达强度明显高于癌旁正常组织(3.28±0.37 vs 1.25±0.64,p<0.01)和腺瘤组织(3.28±0.37 vs 1.13±0.64,P<0.01)。60％结肠腺癌突变型p53呈阳性表达,cFLIP_(short/long)在突变型p53阳性组结肠腺癌中的表达水平明显高于突变型p53阴性组(3.74±0.35 vs 2.58±0.59,P<0.01)。 结论:cFLIP_(short/long)特异性高表达于结肠腺癌组织且在结肠肿瘤转化过程中是一较晚期事件,可能与肿瘤的进展有关。P53突变可使结肠腺癌cFLIP_(short/long)表达水平升高。展开更多
基金supported by grants from the Natural Science Foundation of China(81830049,92269202),National Key R&D Program(2022YFC2304700,2022YFC2303200,2018YFA0507300)Strategic Priority Research Program(XDB29030303)and International Partnership Program(153831KYSB20190008)of the Chinese Academy of Sciences,Shanghai Municipal Science and Technology Major Project(2019SHZDZX02)and Research Leader Program(20XD1403900),as well as the Innovation Capacity Building Project of Jiangsu Province(BM2020019).
文摘The innate immune responses,including inflammasome activation,are paramount for host defense against pathogen infection.In contrast to canonical and noncanonical inflammasome activation,in this study,heat-killed gram-negative bacteria(HK bacteria)were identified as single-step stimulators of the NLRP3 inflammasome in human monocytes,and they caused a moderate amount of IL-1βto be released from cells.Time course experiments showed that this alternative inflammasome response was finished within a few hours.Further analysis showed that the intrinsically limited NLRP3 inflammasome activation response was due to the negative regulation of caspase-8 by the short isoform of cFLIP(cFLIPs),which was activated by NF-κB.In contrast,overexpressed cFLIPS,but not overexpressed cFLIPL,inhibited the activation of caspase-8 and the release of IL-1βin response to HK bacteria infection in human monocytes.Furthermore,we demonstrated that TAK1 activity mediated the expression of cFLIPs and was upstream and essential for the caspase-8 cleavage induced by HK bacteria in human monocytes.The functional specificity of cFLIPs and TAK1 revealed unique responses of human monocytes to a noninvasive pathogen,providing novel insights into an alternative regulatory pathway of NLRP3 inflammasome activation.
文摘目的:检测 cFIP_(short/long)在结肠肿瘤和癌旁组织的表达状况及其与p53基因突变的关系,初步探讨cFLIp在结肠肿瘤发生发展中的意义及p53对其调控作用。 方法:采用免疫组织化学法检测cnLIP在45例结肠腺癌、癌旁组织和42例结肠腺瘤组织中的表达,同时对以上45例结肠腺癌组织行免疫组化染色检测突变p53的表达状况。 cFLIP_(short/long)在结肠腺癌、癌旁组织和腺瘤中的表达差异采用多个样本两两比较的秩和检验(Nemenyi法),cFLIP_(short/long)和突变p53的表达关系采用t检验分析。 结果:cFLIP_(short/long)在结肠腺癌、癌旁组织和腺瘤中都有阳性表达,其染色记分均数分别为3.28±0.37、1.25±0.64和1.13±0.64。结肠腺癌组织的表达强度明显高于癌旁正常组织(3.28±0.37 vs 1.25±0.64,p<0.01)和腺瘤组织(3.28±0.37 vs 1.13±0.64,P<0.01)。60％结肠腺癌突变型p53呈阳性表达,cFLIP_(short/long)在突变型p53阳性组结肠腺癌中的表达水平明显高于突变型p53阴性组(3.74±0.35 vs 2.58±0.59,P<0.01)。 结论:cFLIP_(short/long)特异性高表达于结肠腺癌组织且在结肠肿瘤转化过程中是一较晚期事件,可能与肿瘤的进展有关。P53突变可使结肠腺癌cFLIP_(short/long)表达水平升高。
