Background Recent studies have demonstrated that dexamethasone (DEX) interferes with immune responses by targeting key functions of dendritic cells (DCs) at the earliest stage. However, the cellular and molecular ...Background Recent studies have demonstrated that dexamethasone (DEX) interferes with immune responses by targeting key functions of dendritic cells (DCs) at the earliest stage. However, the cellular and molecular mechanisms are still incompletely understood. This study aimed to explore the possible mechanisms by investigating the roles of DEX on differentiation, maturation & function of murine DCs and the effects of DEX on DCs via Toll-like receptor 4 (TLR4)-nuclear factor (NF)-KB mediated signal pathway. Methods Immature DCs (imDCs) were cultured from murine bone marrow (BM) cells. We added DEX into culture medium at different time. The expression of CD11c, CD86 and I-Ab (mouse MHC class II molecule) was determined by flow cytometry. We determined the expression of NF-κB and its inhibitory protein I-κBα by electrophoretic mobility shift assay (EMSA) and Western blotting, respectively. The productions of interleukin (IL)-12p70 and IL-10 in cell culture supernatants were determined by enzyme-linked immunosorbent assay (ELISA). Results DEX impaired differentiation of DCs from murine bone marrow progenitors, and inhibited lipopolysaccharide (LPS) induced maturation of DCs. DEX significantly inhibited NF-κB expression of normal DCs, the higher the DEX concentration or the longer the DEX treatment time, the more obvious the effect. However, DEX had little effect on LPS-induced NF-KB activation, and partially impaired LPS-induced I-κBα degradation. DEX significantly decreased LPS induced IL-12p70 production by DCs. Interestingly, our results showed a synergistic effect between DEX and LPS on the production of IL-10 by DCs. Conclusions DEX inhibits the differentiation and maturation of murine DCs involved in TLR4-I-κB-NF-κB pathway, and also indirectly impairs Thl development and interferes with the Thl-Th2 balance through IL-12 and/or IL-10 secretion by DCs.展开更多
Decabrominated diphenyl ether(BDE-209)is generally utilized in multiple polymer materials as common brominated flame retardant.BDE-209 has been listed as persistent organic pollutants(POPs),which was considered to be ...Decabrominated diphenyl ether(BDE-209)is generally utilized in multiple polymer materials as common brominated flame retardant.BDE-209 has been listed as persistent organic pollutants(POPs),which was considered to be reproductive toxin in the environment.But it still remains unclear about the effects of BDE-209 on DNA methylation and the inducedmale reproductive toxicity.Due to the extensive epigenetic regulation in germ line development,we hypothesize that BDE-209 exposure impacts the statue of DNA methylation in spermatocytes in vitro.Therefore,the mouse GC-2spd(GC-2)cells were used for the genome wide DNA methylation analysis after treated with 32μg/mL BDE-209 for 24 hr.The results showed that BDE-209 caused genomic methylation changes with 32,083 differentially methylated CpGs in GC-2 cells,including 16,164(50.38%)hypermethylated and 15,919(49.62%)hypomethylated sites.With integrated analysis ofDNAmethylation data and functional enrichment,we found that BDE-209 might affect the functional transcription in cell growth and sperm development by differential gene methylation.qRT-PCR validation demonstrated the involvement of p53-dependent DNA damage response in the GC-2 cells after BDE-209 exposure.In general,our findings indicated that BDE-209-induced genome wide methylation changes could be interrelated with reproductive dysfunction.This study might provide new insights into the mechanisms of male reproductive toxicity under the environmental exposure to BDE-209.展开更多
After dengue virus(DENV)infection,antibody-dependent enhancement(ADE)is easy to occur when the neutralizing antibody(NAb)gradually decreases to a sub-neutralizing concentration.In this cohort surveillance,we utilized ...After dengue virus(DENV)infection,antibody-dependent enhancement(ADE)is easy to occur when the neutralizing antibody(NAb)gradually decreases to a sub-neutralizing concentration.In this cohort surveillance,we utilized sera samples collected from dengue fever patients at different convalescent phases in Jinghong City,to investigate the dynamic change rule of DENV-specific antibodies,and to analyze the risk of ADE caused by secondary infection with heterologous serotypes DENVs.For baseline serosurvey,191 four-year and 99 six-year sera samples during convalescence were collected in 2017 and 2019,respectively.The positive rate of DENVspecific immunoglobulin G was 98.4%in 2017,which significantly decreased to 82.8%in 2019.The geometric mean titer(GMT)of NAb decreased from 1:155.35 to 1:46.66.Among 290 overall samples,73 paired consecutive samples were used for follow-up serosurvey.In four-year sera,the GMTs of NAb against DENV-3 and cross-reactive antibodies against DENV-1,DENV-2 and DENV-4 were 1:167.70,1:13.80,1:18.54 and 1:45.26,respectively,which decreased to 1:53.18,1:10.30,1:14.60 and 1:8.17 in six-year sera.In age-stratified analysis,due to the increasing number of ADE positive samples from 2017 to 2019 in 31–40 and 51–60 years groups,the risk of ADE in DENV-4 infection was positively associated with the extension of convalescent phase,and the odd ratio was higher than other groups.With the recovery period lengthened,the risk of secondary infection with DENV-1 and DENV-2 was reduced.Our results offer essential experimental data for risk prediction of severe dengue in hyper-endemic dengue areas,and provide crucial scientific insight for the development of effective dengue vaccines.展开更多
文摘Background Recent studies have demonstrated that dexamethasone (DEX) interferes with immune responses by targeting key functions of dendritic cells (DCs) at the earliest stage. However, the cellular and molecular mechanisms are still incompletely understood. This study aimed to explore the possible mechanisms by investigating the roles of DEX on differentiation, maturation & function of murine DCs and the effects of DEX on DCs via Toll-like receptor 4 (TLR4)-nuclear factor (NF)-KB mediated signal pathway. Methods Immature DCs (imDCs) were cultured from murine bone marrow (BM) cells. We added DEX into culture medium at different time. The expression of CD11c, CD86 and I-Ab (mouse MHC class II molecule) was determined by flow cytometry. We determined the expression of NF-κB and its inhibitory protein I-κBα by electrophoretic mobility shift assay (EMSA) and Western blotting, respectively. The productions of interleukin (IL)-12p70 and IL-10 in cell culture supernatants were determined by enzyme-linked immunosorbent assay (ELISA). Results DEX impaired differentiation of DCs from murine bone marrow progenitors, and inhibited lipopolysaccharide (LPS) induced maturation of DCs. DEX significantly inhibited NF-κB expression of normal DCs, the higher the DEX concentration or the longer the DEX treatment time, the more obvious the effect. However, DEX had little effect on LPS-induced NF-KB activation, and partially impaired LPS-induced I-κBα degradation. DEX significantly decreased LPS induced IL-12p70 production by DCs. Interestingly, our results showed a synergistic effect between DEX and LPS on the production of IL-10 by DCs. Conclusions DEX inhibits the differentiation and maturation of murine DCs involved in TLR4-I-κB-NF-κB pathway, and also indirectly impairs Thl development and interferes with the Thl-Th2 balance through IL-12 and/or IL-10 secretion by DCs.
基金supported by the National Natural Science Foundation of China(Nos.31770441,31971415).
文摘Decabrominated diphenyl ether(BDE-209)is generally utilized in multiple polymer materials as common brominated flame retardant.BDE-209 has been listed as persistent organic pollutants(POPs),which was considered to be reproductive toxin in the environment.But it still remains unclear about the effects of BDE-209 on DNA methylation and the inducedmale reproductive toxicity.Due to the extensive epigenetic regulation in germ line development,we hypothesize that BDE-209 exposure impacts the statue of DNA methylation in spermatocytes in vitro.Therefore,the mouse GC-2spd(GC-2)cells were used for the genome wide DNA methylation analysis after treated with 32μg/mL BDE-209 for 24 hr.The results showed that BDE-209 caused genomic methylation changes with 32,083 differentially methylated CpGs in GC-2 cells,including 16,164(50.38%)hypermethylated and 15,919(49.62%)hypomethylated sites.With integrated analysis ofDNAmethylation data and functional enrichment,we found that BDE-209 might affect the functional transcription in cell growth and sperm development by differential gene methylation.qRT-PCR validation demonstrated the involvement of p53-dependent DNA damage response in the GC-2 cells after BDE-209 exposure.In general,our findings indicated that BDE-209-induced genome wide methylation changes could be interrelated with reproductive dysfunction.This study might provide new insights into the mechanisms of male reproductive toxicity under the environmental exposure to BDE-209.
基金supported by the National Natural Science Foundation of China under grants 81772172,U1902210,81972979 and 81902048
文摘After dengue virus(DENV)infection,antibody-dependent enhancement(ADE)is easy to occur when the neutralizing antibody(NAb)gradually decreases to a sub-neutralizing concentration.In this cohort surveillance,we utilized sera samples collected from dengue fever patients at different convalescent phases in Jinghong City,to investigate the dynamic change rule of DENV-specific antibodies,and to analyze the risk of ADE caused by secondary infection with heterologous serotypes DENVs.For baseline serosurvey,191 four-year and 99 six-year sera samples during convalescence were collected in 2017 and 2019,respectively.The positive rate of DENVspecific immunoglobulin G was 98.4%in 2017,which significantly decreased to 82.8%in 2019.The geometric mean titer(GMT)of NAb decreased from 1:155.35 to 1:46.66.Among 290 overall samples,73 paired consecutive samples were used for follow-up serosurvey.In four-year sera,the GMTs of NAb against DENV-3 and cross-reactive antibodies against DENV-1,DENV-2 and DENV-4 were 1:167.70,1:13.80,1:18.54 and 1:45.26,respectively,which decreased to 1:53.18,1:10.30,1:14.60 and 1:8.17 in six-year sera.In age-stratified analysis,due to the increasing number of ADE positive samples from 2017 to 2019 in 31–40 and 51–60 years groups,the risk of ADE in DENV-4 infection was positively associated with the extension of convalescent phase,and the odd ratio was higher than other groups.With the recovery period lengthened,the risk of secondary infection with DENV-1 and DENV-2 was reduced.Our results offer essential experimental data for risk prediction of severe dengue in hyper-endemic dengue areas,and provide crucial scientific insight for the development of effective dengue vaccines.