T-2毒素免疫毒性研究现状
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摘要
T-2毒素的免疫毒性具有矛盾性和复杂性。低剂量T-2毒素可提升动物对病原体的抵抗力,高剂量T-2毒素则大大降低动物的免疫力。T-2毒素暴露时间早于病原体可增加动物免疫抵抗力,反之或毒素与病原体同时暴露,则降低动物对病原体的抵抗力。近期研究发现,细胞凋亡/存活通路维持毒素免疫调控动态平衡,自噬在免疫调控中发挥着关键而复杂的作用,但T-2毒素免疫调控中是否存在类似"免疫逃避"机制亟待研究。论文综述了T-2毒素免疫毒性的矛盾性,并重点讨论了其潜在的分子机制,为单端孢霉烯族毒素的免疫毒性和动物疫病防控研究提供参考。
T-2 toxin shows a Janus face in the immunotoxicity:immunosuppressive and immunostimulatory effects coexist.The dose and duration of T-2 toxin are key factors.Basically,low-dose toxin significantly increases host resistance to pathogens,whereas high-dose greatly reduces immunity.That exposure to T-2 toxin earlier than pathogens increases the animal's immune resistance;conversely,or toxins and pathogens exposed at the same time will reduce the animals' resistance to pathogens.Increasing lines of evidence show:(1)Competition in cell apoptosis/survival signaling pathways maintains immune balance;(2)Autophagy plays a key but complex role in the immune regulation;(3)Whether an immune evasion mechanism exists in the immune regulation of this toxin is also urgently need to study.In this review,we discussed the progress on immunomodulatory effect of T-2 toxin.The potential mechanisms of T-2 toxin-mediated paradoxical immunotoxicity were further discussed.We hope this review may provide further information on the understanding of the immunotoxicity of T-2 toxin and shed new light on the prevention and controlling of animal diseases caused by trichothecenes.
T-2 toxin shows a Janus face in the immunotoxicity:immunosuppressive and immunostimulatory effects coexist.The dose and duration of T-2 toxin are key factors.Basically,low-dose toxin significantly increases host resistance to pathogens,whereas high-dose greatly reduces immunity.That exposure to T-2 toxin earlier than pathogens increases the animal's immune resistance;conversely,or toxins and pathogens exposed at the same time will reduce the animals' resistance to pathogens.Increasing lines of evidence show:(1)Competition in cell apoptosis/survival signaling pathways maintains immune balance;(2)Autophagy plays a key but complex role in the immune regulation;(3)Whether an immune evasion mechanism exists in the immune regulation of this toxin is also urgently need to study.In this review,we discussed the progress on immunomodulatory effect of T-2 toxin.The potential mechanisms of T-2 toxin-mediated paradoxical immunotoxicity were further discussed.We hope this review may provide further information on the understanding of the immunotoxicity of T-2 toxin and shed new light on the prevention and controlling of animal diseases caused by trichothecenes.
引文
[1]Guo P,Liu A,Huang D,et al.Brain damage and neurological symptoms induced by T-2toxin in rat brain[J].Toxicol Lett,2018,286:96-107.
[2]Chen H Y,Rawlings R.亚洲地区饲料原料和配合饲料中霉菌毒素水平的调查[J].饲料研究,2008(9):28-31.
[3]Liu X,Guo P,Liu A,et al.Nitric oxide(NO)-mediated mitochondrial damage plays a critical role in T-2toxin-induced apoptosis and growth hormone deficiency in rat anterior pituitary GH3cells[J].Food Chem Toxicol,2017,102:11-23.
[4]吴庆华.T-2毒素的代谢和毒作用信号转导研究[D].湖北武汉:华中农业大学,2014.
[5]Wu Q H,Wang X,Yang W,et al.Oxidative stress-mediated cytotoxicity and metabolism of T-2toxin and deoxynivalenol in animals and humans:an update[J].Arch Toxicol,2014,88(7):1309-1326.
[6]GaigéS,Djelloul M,Tardivel C,et al.Modification of energy balance induced by the food contaminant T-2toxin:a multimodal gut-to-brain connection[J].Brain Behav Immun,2014,37:54-72.
[7]Clark E S,Flannery B M,Gardner E M,et al.High sensitivity of aged mice to deoxynivalenol(vomitoxin)-induced anorexia corresponds to elevated proinflammatory cytokine and satiety hormone responses[J].Toxins,2015,7:4199-4215.
[8]Male D,Wu W,Mitchell N J,et al.Modeling the emetic potencies of food-borne trichothecenes by benchmark dose methodology[J].Food Chem Toxicol,2016,94:178-185.
[9]Zhou H R,He K,Landgraf J,et al.Direct activation of ribosome-associated double-stranded RNA-dependent protein kinase(PKR)by deoxynivalenol,anisomycin and ricin:a new model for ribotoxic stress response induction[J].Toxins,2014,6(12):3406-3425.
[10]Fang H,Cong L,Zhi Y,et al.T-2toxin inhibits murine ES cells cardiac differentiation and mitochondrial biogenesis by ROS and p-38 MAPK-mediated pathway[J].Toxicol Lett,2016,258:259-266.
[11]Wu J,Jing L,Yuan H,et al.T-2toxin induces apoptosis in ovarian granulosa cells of rats through reactive oxygen speciesmediated mitochondrial pathway[J].Toxicol Lett,2011,202(3):168-177.
[12]Yuan G,Wang Y,Yuan X,et al.T-2toxin induces developmental toxicity and apoptosis in zebrafish embryos[J].J Environ Sci(China),2014,26(4):917-925.
[13]Yang S,Li Y,Cao X,et al.Metabolic pathways of T-2toxin in in vivo and in vitro systems of Wistar rats[J].J Agri Food Chem,2013,61(40):9734-9743.
[14]Ma S,Zhao Y,Sun J,et al.miR449a/SIRT1/PGC-1αis necessary for mitochondrial biogenesis induced by T-2toxin[J].Front Pharmacol,2017,8:954
[15]Liu X,Wen J,Chen R,et al.T-2toxin induces the expression of porcine CYP3A22via the upregulation of the transcription factor,NF-Y[J].Biochim Biophys Acta,2016,1860(10):2191-2201.
[16]Wu Q,Wang X,Wan D,et al.Crosstalk of JNK1-STAT3is critical for RAW264.7cell survival[J].Cell Signal,2014,26:2951-2960.
[17]Liu X,Huang D,Guo P,et al.PKA/CREB and NF-kappaB pathway regulates AKNA transcription:A novel insight into T-2toxin-induced inflammation and GH deficiency in GH3cells[J].Toxicology,2017,392:81-95.
[18]Guo P,Liu A,Huang D,et al.Brain damage and neurological symptoms induced by T-2toxin in rat brain[J].Toxicol Lett,2018,286:96-107.
[19]Liu J,Wang L,Guo X,et al.The role of mitochondria in T-2toxin-induced human chondrocytes apoptosis[J].PLoS One,2014,9(9):e108394.
[20]Zhang Y,Jia R X,Pan M H,et al.HT-2toxin affects development of porcine parthenotes by altering DNA and histone methylation in oocytes matured in vitro[J].Theriogenology,2017,103:110-116.
[21]Wu W,Sheng K,Xu X,et al.Potential roles for glucagon-like peptide-17-36amide and cholecystokinin in anorectic response to the trichothecene mycotoxin T-2toxin[J].Ecotox Environ Safety,2018,153:181-187.
[22]Deng Q,Qiu M,Wang Y,et al.A sensitive and validated immunomagnetic-bead based enzyme-linked immunosorbent assay for analyzing total T-2(free and modified)toxins in shrimp tissues[J].Ecotox Environ Safety,2017,142:441-447.
[23]Pestka J J,Zhou H R,Moon Y,et al.Cellular and molecular mechanisms for immune modulation by deoxynivalenol and other trichothecenes:unraveling aparadox[J].Toxicol Lett,2004,153:61-73.
[24]Li S J,Pasmans F,Croubels S,et al.T-2toxin impairs antifungal activities of chicken macrophages against Aspergillus fumigatus conidia but promotes the pro-inflammatory responses[J].Avian Pathol,2013,42(5):457-463.
[25]Corrier D E,Ziprin R L,Mollenhauer H H.Modulation of cellmediated resistance to listeriosis in mice given T-2toxin[J].Toxicol Appl Pharmacol,1987,89(3):323-331.
[26]Savard C,Pinilla V,Provost C,et al.In vivo effect of deoxynivalenol(DON)naturally contaminated feed on porcine reproductive and respiratory syndrome virus(PRRSV)infection[J].Vet Microbiol,2014,174(3-4):419-426.
[27]Pestka J J.Deoxynivalenol:mechanisms of action,human exposure,and toxicological relevance[J].Arch Toxicol,2010,84:663-679.
[28]Tang Y,Li J,Li F,et al.Autophagy protects intestinal epithelial cells against deoxynivalenol toxicity by alleviating oxidative stress via IKK signaling pathway[J].Free Radical Bio Med,2015,89:944-951.
[29]Paquette M,El-Houjeiri L,Pause A.mTOR Pathways in cancer and autophagy[J].Cancers,2018,10(1):18.
[30]Spranger S,Gajewski T F.Impact of oncogenic pathways on evasion of antitumour immune responses[J].Nat Rev Cancer,2018,18(3):139-147.
[31]Sugiyama K,Muroi M,Tanamoto K,et al.Deoxynivalenol and nivalenol inhibit lipopolysaccharide-induced nitric oxide production by mouse macrophage cells[J].Toxicol Lett,2010,192(2):150-154.
[32]Sugiyama K,Muroi M,Kinoshita M,et al.NF-κB activation via MyD88-dependent Toll-like receptor signaling is inhibited by trichothecene mycotoxin deoxynivalenol[J].J Toxicol Sci,2016 41(2):273-279.
[33]Wu Q,Wang X,Nepovimova E,et al.Trichothecenes:immunomodulatory effects,mechanisms,and anti-cancer potential[J].Arch Toxicol,2017,91:3737-3785.
[2]Chen H Y,Rawlings R.亚洲地区饲料原料和配合饲料中霉菌毒素水平的调查[J].饲料研究,2008(9):28-31.
[3]Liu X,Guo P,Liu A,et al.Nitric oxide(NO)-mediated mitochondrial damage plays a critical role in T-2toxin-induced apoptosis and growth hormone deficiency in rat anterior pituitary GH3cells[J].Food Chem Toxicol,2017,102:11-23.
[4]吴庆华.T-2毒素的代谢和毒作用信号转导研究[D].湖北武汉:华中农业大学,2014.
[5]Wu Q H,Wang X,Yang W,et al.Oxidative stress-mediated cytotoxicity and metabolism of T-2toxin and deoxynivalenol in animals and humans:an update[J].Arch Toxicol,2014,88(7):1309-1326.
[6]GaigéS,Djelloul M,Tardivel C,et al.Modification of energy balance induced by the food contaminant T-2toxin:a multimodal gut-to-brain connection[J].Brain Behav Immun,2014,37:54-72.
[7]Clark E S,Flannery B M,Gardner E M,et al.High sensitivity of aged mice to deoxynivalenol(vomitoxin)-induced anorexia corresponds to elevated proinflammatory cytokine and satiety hormone responses[J].Toxins,2015,7:4199-4215.
[8]Male D,Wu W,Mitchell N J,et al.Modeling the emetic potencies of food-borne trichothecenes by benchmark dose methodology[J].Food Chem Toxicol,2016,94:178-185.
[9]Zhou H R,He K,Landgraf J,et al.Direct activation of ribosome-associated double-stranded RNA-dependent protein kinase(PKR)by deoxynivalenol,anisomycin and ricin:a new model for ribotoxic stress response induction[J].Toxins,2014,6(12):3406-3425.
[10]Fang H,Cong L,Zhi Y,et al.T-2toxin inhibits murine ES cells cardiac differentiation and mitochondrial biogenesis by ROS and p-38 MAPK-mediated pathway[J].Toxicol Lett,2016,258:259-266.
[11]Wu J,Jing L,Yuan H,et al.T-2toxin induces apoptosis in ovarian granulosa cells of rats through reactive oxygen speciesmediated mitochondrial pathway[J].Toxicol Lett,2011,202(3):168-177.
[12]Yuan G,Wang Y,Yuan X,et al.T-2toxin induces developmental toxicity and apoptosis in zebrafish embryos[J].J Environ Sci(China),2014,26(4):917-925.
[13]Yang S,Li Y,Cao X,et al.Metabolic pathways of T-2toxin in in vivo and in vitro systems of Wistar rats[J].J Agri Food Chem,2013,61(40):9734-9743.
[14]Ma S,Zhao Y,Sun J,et al.miR449a/SIRT1/PGC-1αis necessary for mitochondrial biogenesis induced by T-2toxin[J].Front Pharmacol,2017,8:954
[15]Liu X,Wen J,Chen R,et al.T-2toxin induces the expression of porcine CYP3A22via the upregulation of the transcription factor,NF-Y[J].Biochim Biophys Acta,2016,1860(10):2191-2201.
[16]Wu Q,Wang X,Wan D,et al.Crosstalk of JNK1-STAT3is critical for RAW264.7cell survival[J].Cell Signal,2014,26:2951-2960.
[17]Liu X,Huang D,Guo P,et al.PKA/CREB and NF-kappaB pathway regulates AKNA transcription:A novel insight into T-2toxin-induced inflammation and GH deficiency in GH3cells[J].Toxicology,2017,392:81-95.
[18]Guo P,Liu A,Huang D,et al.Brain damage and neurological symptoms induced by T-2toxin in rat brain[J].Toxicol Lett,2018,286:96-107.
[19]Liu J,Wang L,Guo X,et al.The role of mitochondria in T-2toxin-induced human chondrocytes apoptosis[J].PLoS One,2014,9(9):e108394.
[20]Zhang Y,Jia R X,Pan M H,et al.HT-2toxin affects development of porcine parthenotes by altering DNA and histone methylation in oocytes matured in vitro[J].Theriogenology,2017,103:110-116.
[21]Wu W,Sheng K,Xu X,et al.Potential roles for glucagon-like peptide-17-36amide and cholecystokinin in anorectic response to the trichothecene mycotoxin T-2toxin[J].Ecotox Environ Safety,2018,153:181-187.
[22]Deng Q,Qiu M,Wang Y,et al.A sensitive and validated immunomagnetic-bead based enzyme-linked immunosorbent assay for analyzing total T-2(free and modified)toxins in shrimp tissues[J].Ecotox Environ Safety,2017,142:441-447.
[23]Pestka J J,Zhou H R,Moon Y,et al.Cellular and molecular mechanisms for immune modulation by deoxynivalenol and other trichothecenes:unraveling aparadox[J].Toxicol Lett,2004,153:61-73.
[24]Li S J,Pasmans F,Croubels S,et al.T-2toxin impairs antifungal activities of chicken macrophages against Aspergillus fumigatus conidia but promotes the pro-inflammatory responses[J].Avian Pathol,2013,42(5):457-463.
[25]Corrier D E,Ziprin R L,Mollenhauer H H.Modulation of cellmediated resistance to listeriosis in mice given T-2toxin[J].Toxicol Appl Pharmacol,1987,89(3):323-331.
[26]Savard C,Pinilla V,Provost C,et al.In vivo effect of deoxynivalenol(DON)naturally contaminated feed on porcine reproductive and respiratory syndrome virus(PRRSV)infection[J].Vet Microbiol,2014,174(3-4):419-426.
[27]Pestka J J.Deoxynivalenol:mechanisms of action,human exposure,and toxicological relevance[J].Arch Toxicol,2010,84:663-679.
[28]Tang Y,Li J,Li F,et al.Autophagy protects intestinal epithelial cells against deoxynivalenol toxicity by alleviating oxidative stress via IKK signaling pathway[J].Free Radical Bio Med,2015,89:944-951.
[29]Paquette M,El-Houjeiri L,Pause A.mTOR Pathways in cancer and autophagy[J].Cancers,2018,10(1):18.
[30]Spranger S,Gajewski T F.Impact of oncogenic pathways on evasion of antitumour immune responses[J].Nat Rev Cancer,2018,18(3):139-147.
[31]Sugiyama K,Muroi M,Tanamoto K,et al.Deoxynivalenol and nivalenol inhibit lipopolysaccharide-induced nitric oxide production by mouse macrophage cells[J].Toxicol Lett,2010,192(2):150-154.
[32]Sugiyama K,Muroi M,Kinoshita M,et al.NF-κB activation via MyD88-dependent Toll-like receptor signaling is inhibited by trichothecene mycotoxin deoxynivalenol[J].J Toxicol Sci,2016 41(2):273-279.
[33]Wu Q,Wang X,Nepovimova E,et al.Trichothecenes:immunomodulatory effects,mechanisms,and anti-cancer potential[J].Arch Toxicol,2017,91:3737-3785.