AIM: To investigate whether induction of tolerance of mice to lipopolysaccharide (LPS) was able to inhibit apoptotic reaction in terms of characteristic DNA fragmentation and protect mice from lethal effect. METHODS: ...AIM: To investigate whether induction of tolerance of mice to lipopolysaccharide (LPS) was able to inhibit apoptotic reaction in terms of characteristic DNA fragmentation and protect mice from lethal effect. METHODS: Experimental groups of mice were pretreated with non-lethal amount of LPS (0.05 μg). Both control and experimental groups simultaneously were challenged with LPS plus D-GaIN for 6-7 h. The evaluations of both DNA fragmentations from the livers and the protection efficacy against lethality to mice through induction of tolerance to LPS were conducted. RESULTS: In the naive mice challenge with LPS plus D-GaIN resulted in complete death in 24 h, whereas a characteristic apoptotic DNA fragmentation was exclusively seen in the livers of mice receiving LPS in combination with D-GaIN. The mortality in the affected mice was closely correlated to the onset of DNA fragmentation. By contrast, in the mice pre-exposed to LPS, both lethal effect and apoptotic DNA fragmentation were suppressed when challenged with LPS/D-GalN. In addition to LPS, the induction of mouse tolerance to TNF also enabled mice to cross-react against death and apoptotic DNA fragmentation when challenged with TNF and/or LPS in the presence of D-GaIN. Moreover, this protection effect by LPS could last up to 24 h. TNFR1 rather than TNFR2 played a dual role in signaling pathway of either induction of tolerance to LPS for the protection of mice from mortality or inducing morbidity leading to the death of mice. CONCLUSION: The mortality of D-GalN-treated mice in response to LPS was exceedingly correlated to the onset of apoptosis in the liver, which can be effectively suppressed by brief exposure of mice to a minute amount of LPS. The induced tolerance status was mediated not only by LPS but also by TNF. The developed tolerance to either LPS or TNF can be reciprocally cross-reacted between LPS and TNF challenges, whereas the signaling of induction of tolerance and promotion of apoptosis was through TNFR1, rather than TNFR2.展开更多
Tumor necrosis factors(TNFs)are a group of cytokines that play critical roles in regulating a diverse range of physiological processes in vertebrates.TNFs function by activating a large number of structurally related ...Tumor necrosis factors(TNFs)are a group of cytokines that play critical roles in regulating a diverse range of physiological processes in vertebrates.TNFs function by activating a large number of structurally related receptors,leading to TNF mediated biological processes which are evolutionarily conserved.Fish have a much diversified TNF family,partly due to the whole genome duplication events which have occurred in this lineage,providing an excellent model to investigate the neo-and subfunctionalised properties of TNF superfamily.Fish possess most of the TNFs and receptors found in mammals and also some homologues exclusively present in fish.It seems that TNFSF4(OX40),TNFSF7(CD27)and TNFSF8(CD30)and their cognate receptors are absent in teleosts.It has been shown that fish viruses are able to produce TNFR homologues to establish infection by manipulating the host immune system.Understanding the roles of TNFSFs in fish immune defence and the pathogenesis of fish diseases will provide insights into the functions of TNFSFs from an evolutionary perspective and better strategies for improving fish health and welfare in aquaculture.This review summarises recent advances in the study of fish TNF biology and focuses on the molecular properties and immunological functions of the TNF and TNFR superfamily.展开更多
Tumor necrosis factor(TNF)and its receptors TNF receptor type 1(TNFR1)and type 2(TNFR2)have a central role in chronic inflammatory diseases.While TNFR1 mainly confers inflammation,activation of TNFR2 elicits not only ...Tumor necrosis factor(TNF)and its receptors TNF receptor type 1(TNFR1)and type 2(TNFR2)have a central role in chronic inflammatory diseases.While TNFR1 mainly confers inflammation,activation of TNFR2 elicits not only pro-inflammatory but also anti-inflammatory effects.In this study,we wanted to investigate the anti-inflammatory therapeutic potential of selective activation of TNFR2 in mice with established collageninduced arthritis.Mice with established arthritis induced by immunization with bovine collagen type II were treated with six injections of the TNFR2-specific agonist TNCscTNF80,given every second day.Two days after treatment cessation,the cell compositions of bone marrow,spleen and lymph nodes were analyzed.Mice were visually scored until day 30 after the start of therapy and the degree of joint inflammation was determined by histology.Treatment with TNCscTNF80 increased arthritis-induced myelopoiesis.Little effect was seen on the infiltration rate of inflammatory immature myeloid cells and on the reduction of lymphoid cells in secondary lymphoid organs.Upon treatment,frequency of regulatory T(Treg)cells in the CD4+T-cell population was increased in both spleen and inguinal lymph nodes.In addition,the expression of TNFR2 on Treg cells was enhanced.The clinical score started to improve 1 week after cessation treatment and remained lower 30 days after initiation of therapy.The histological score also revealed amelioration of joint inflammation in TNCscTNF80-treated versus control mice.Activation of TNFR2 might provide a suitable therapeutic strategy in autoimmune arthritis by increasing the numbers of regulatory cell types,in particular Treg cells,and by attenuation of arthritis.展开更多
基金Supported by a fellowship (to Zhou B) from Max-Planck-Society, Germany, and partially supported by the National Key Basic ResearchDevelopment Program (973 Program) of China, No. 2002CB513006 (to Zhou B)
文摘AIM: To investigate whether induction of tolerance of mice to lipopolysaccharide (LPS) was able to inhibit apoptotic reaction in terms of characteristic DNA fragmentation and protect mice from lethal effect. METHODS: Experimental groups of mice were pretreated with non-lethal amount of LPS (0.05 μg). Both control and experimental groups simultaneously were challenged with LPS plus D-GaIN for 6-7 h. The evaluations of both DNA fragmentations from the livers and the protection efficacy against lethality to mice through induction of tolerance to LPS were conducted. RESULTS: In the naive mice challenge with LPS plus D-GaIN resulted in complete death in 24 h, whereas a characteristic apoptotic DNA fragmentation was exclusively seen in the livers of mice receiving LPS in combination with D-GaIN. The mortality in the affected mice was closely correlated to the onset of DNA fragmentation. By contrast, in the mice pre-exposed to LPS, both lethal effect and apoptotic DNA fragmentation were suppressed when challenged with LPS/D-GalN. In addition to LPS, the induction of mouse tolerance to TNF also enabled mice to cross-react against death and apoptotic DNA fragmentation when challenged with TNF and/or LPS in the presence of D-GaIN. Moreover, this protection effect by LPS could last up to 24 h. TNFR1 rather than TNFR2 played a dual role in signaling pathway of either induction of tolerance to LPS for the protection of mice from mortality or inducing morbidity leading to the death of mice. CONCLUSION: The mortality of D-GalN-treated mice in response to LPS was exceedingly correlated to the onset of apoptosis in the liver, which can be effectively suppressed by brief exposure of mice to a minute amount of LPS. The induced tolerance status was mediated not only by LPS but also by TNF. The developed tolerance to either LPS or TNF can be reciprocally cross-reacted between LPS and TNF challenges, whereas the signaling of induction of tolerance and promotion of apoptosis was through TNFR1, rather than TNFR2.
基金funded by the National Key R&D Program of China(2018YFD0900302),National Natural Science Foundation of China(31802288,31572615)China Postdoctoral Science Foundation(2017M612560,2018T110833)。
文摘Tumor necrosis factors(TNFs)are a group of cytokines that play critical roles in regulating a diverse range of physiological processes in vertebrates.TNFs function by activating a large number of structurally related receptors,leading to TNF mediated biological processes which are evolutionarily conserved.Fish have a much diversified TNF family,partly due to the whole genome duplication events which have occurred in this lineage,providing an excellent model to investigate the neo-and subfunctionalised properties of TNF superfamily.Fish possess most of the TNFs and receptors found in mammals and also some homologues exclusively present in fish.It seems that TNFSF4(OX40),TNFSF7(CD27)and TNFSF8(CD30)and their cognate receptors are absent in teleosts.It has been shown that fish viruses are able to produce TNFR homologues to establish infection by manipulating the host immune system.Understanding the roles of TNFSFs in fish immune defence and the pathogenesis of fish diseases will provide insights into the functions of TNFSFs from an evolutionary perspective and better strategies for improving fish health and welfare in aquaculture.This review summarises recent advances in the study of fish TNF biology and focuses on the molecular properties and immunological functions of the TNF and TNFR superfamily.
基金Part of the work has been funded by the Deutsche Forschungsgemeinschaft with grants to RHS(STR 511/32-1)and HW(WA 1025/31-1)Additionally,the work has been funded by the respective institutions.
文摘Tumor necrosis factor(TNF)and its receptors TNF receptor type 1(TNFR1)and type 2(TNFR2)have a central role in chronic inflammatory diseases.While TNFR1 mainly confers inflammation,activation of TNFR2 elicits not only pro-inflammatory but also anti-inflammatory effects.In this study,we wanted to investigate the anti-inflammatory therapeutic potential of selective activation of TNFR2 in mice with established collageninduced arthritis.Mice with established arthritis induced by immunization with bovine collagen type II were treated with six injections of the TNFR2-specific agonist TNCscTNF80,given every second day.Two days after treatment cessation,the cell compositions of bone marrow,spleen and lymph nodes were analyzed.Mice were visually scored until day 30 after the start of therapy and the degree of joint inflammation was determined by histology.Treatment with TNCscTNF80 increased arthritis-induced myelopoiesis.Little effect was seen on the infiltration rate of inflammatory immature myeloid cells and on the reduction of lymphoid cells in secondary lymphoid organs.Upon treatment,frequency of regulatory T(Treg)cells in the CD4+T-cell population was increased in both spleen and inguinal lymph nodes.In addition,the expression of TNFR2 on Treg cells was enhanced.The clinical score started to improve 1 week after cessation treatment and remained lower 30 days after initiation of therapy.The histological score also revealed amelioration of joint inflammation in TNCscTNF80-treated versus control mice.Activation of TNFR2 might provide a suitable therapeutic strategy in autoimmune arthritis by increasing the numbers of regulatory cell types,in particular Treg cells,and by attenuation of arthritis.
