Abstract
Paradoxically, trichothecenes have both immunosuppressive and immunostimulatory effects. The underlying mechanisms have not been fully explored. Early studies show that dose, exposure timing, and the time at which immune function is assessed influence whether trichothecenes act in an immunosuppressive or immunostimulatory fashion. Recent studies suggest that the immunomodulatory function of trichothecenes is also actively shaped by competing cell-survival and death-signaling pathways. Autophagy may also promote trichothecene immunosuppression, although the mechanism may be complicated. Moreover, trichothecenes may generate an “immune evasion” milieu that allows pathogens to escape host and vaccine immune defenses. Some trichothecenes, especially macrocyclic trichothecenes, also potently kill cancer cells. T-2 toxin conjugated with anti-cancer monoclonal antibodies significantly suppresses the growth of thymoma EL-4 cells and colon cancer cells. The type B trichothecene diacetoxyscirpenol specifically inhibits the tumor-promoting factor HIF-1 in cancer cells under hypoxic conditions. Trichothecin markedly inhibits the growth of multiple cancer cells with constitutively activated NF-κB. The type D macrocyclic toxin Verrucarin A is also a promising therapeutic candidate for leukemia, breast cancer, prostate cancer, and pancreatic cancer. The anti-cancer activities of trichothecenes have not been comprehensively summarized. Here, we first summarize the data on the immunomodulatory effects of trichothecenes and discuss recent studies that shed light on the underlying cellular and molecular mechanisms. These mechanisms include autophagy and major signaling pathways and their crosstalk. Second, the anti-cancer potential of trichothecenes and the underlying mechanisms will be discussed. We hope that this review will show how trichothecene bioactivities can be exploited to generate therapies against pathogens and cancer.
Similar content being viewed by others
Abbreviations
- ARNT:
-
Aryl hydrocarbon receptor nuclear translocator
- CaSR:
-
Calcium-sensing receptor
- CDC:
-
Complement-dependent cytotoxicity
- CHOP:
-
Enhancer-binding protein homologous protein
- CREB:
-
cAMP-response clement-binding protein
- DAS:
-
Diacetoxyscirpenol
- DMBA:
-
7,12-Dimethylbenz[a]anthracene
- DON:
-
Deoxynivalenol
- FB1:
-
Fumonisin B1
- FX:
-
Fusarenon X
- GFP:
-
Green fluorescence protein
- GSH:
-
Glutathione
- Hck:
-
Hemopoietic cell kinase
- HIF-1:
-
Hypoxia-inducible factor 1
- mAb:
-
Monoclonal antibodies
- MIP-2:
-
Macrophage inhibitory protein 2
- MyD88:
-
Myeloid differentiation factor 88
- NIV:
-
Nivalenol
- PCD:
-
Programmed cell death
- PCV2:
-
Porcine circovirus type 2
- PCVAD:
-
Porcine circovirus-associated disease
- PI:
-
Post-injection
- PKR:
-
RNA-activated protein kinase R
- PMNs:
-
Pig polymorphonuclear cells
- PP:
-
Peyer’s patch
- PRRS:
-
Porcine reproductive and respiratory syndrome
- PRRSV:
-
Porcine reproductive and respiratory syndrome virus
- PTPC:
-
Permeability transition pore complex
- QSAR:
-
Quantitative structure activity relationship
- RBC:
-
Sheep red blood cell
- RSR:
-
Ribotoxic stress response
- SAR:
-
Structure–activity relationships
- SMI:
-
Mall molecule inhibitors
- SRC:
-
Steroid receptor coactivator
- TCN:
-
Trichothecin
- TLR:
-
Toll-like Receptors
- TPA:
-
12-O-tetradecanoylphorbol-13-acetate
- TRAIL:
-
TNF-related apoptosis-inducing ligand
- TRPA1:
-
Transient receptor potential ankyrin-1
- VA:
-
Verrucarins A
References
Abbas HK, Johnson BB, Shier WT et al (2002) Phytotoxicity and mammalian cytotoxicity of macrocyclic trichothecene mycotoxins from Myrothecium verrucaria. Phytochemistry 59(3):309–313
Abbas HK, Yoshizawa T, Shier WT (2013) Cytotoxicity and phytotoxicity of trichothecene mycotoxins produced by Fusarium spp.. Toxicon 74:68–75
Agrawal M, Yadav P, Lomash V et al (2012) T-2 toxin induced skin inflammation and cutaneous injury in mice. Toxicology 302(2–3):255–265
Agrawal M, Bhaskar ASB, Rao PVL (2015) Involvement of mitogen-activated protein kinase pathway in T-2 toxin-induced cell cycle alteration and apoptosis in human neuroblastoma cells. Mol Neurobiol 51:1379–1394
Akira S, Takeda K, Kaisho T et al (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2(8):675–680
Alassane-Kpembi I, Puel O, Pinton P et al (2017) Co-exposure to low doses of the food contaminants deoxynivalenol and nivalenol has a synergistic inflammatory effect on intestinal explants. Arch Toxicol 91(7):2677–2687
Alcami A, Koszinowski UH (2000) Viral mechanisms of immune evasion. Mol Med Today 6(9):365–372
Aleksic B, Bailly S, Draghi M et al (2016) Production of four macrocyclic trichothecenes by Stachybotrys chartarum during its development on different building materials as measured by UPLC-MS/MS. Build Environ 106:265–273
Allahyari H, Heidari S, Ghamgosha M et al (2017) Immunotoxin: a new tool for cancer therapy. Tumor Biol 39(2):1010428317692226
Alvarado AG, Lathia JD (2016) Taking a toll on self-renewal: TLR-mediated innate immune signaling in stem cells. Trends Neurosci 39(7):463–471
Amagata T, Rath C, Rigot JF et al (2003) Structures and cytotoxic properties of trichoverroids and their macrolide analogues produced by saltwater culture of Myrothecium verrucaria. J Med Chem 46(20):4342–4350
Antignani A, FitzGerald D (2013) Immunotoxins: the role of the toxin. Toxins 5(8):1486–1502
Antonissen G, Haesendonck R, Devreese M et al (2016) The impact of deoxynivalenol on pigeon health: occurrence in feed, toxicokinetics and interaction with Salmonellosis. PLoS One 11(12):e0168205
Appell M, Bosma WB (2015) Assessment of the electronic structure and properties of trichothecene toxins using density functional theory. J Hazard Mater 288:113–23
Arai KI, Lee F, Miyajima A et al (1990) Cytokines: coordinators of immune and inflammatory responses. Annu Rev Biochem 59:783–836
Atroshi F, Rizzo AF, Veijalainen P et al (1994) The effect of dietary exposure to DON and T-2 Toxin on host resistance and serum immunoglobins of normal and mastitic mice. J Anim Physiol Anim N 71(1–5):223–233
Aupanun S, Phuektes P, Poapolathep S et al (2016) Apoptosis and gene expression in Jurkat human T cells and lymphoid tissues of fusarenon-X-treated mice. Toxicon 123:15–24
Aupanun S, Poapolathep S, Giorgi M et al (2017) An overview of the toxicology and toxicokinetics of fusarenon-X, a type B trichothecene mycotoxin. J Vet Med Sci 79(1):6–13
Bae HK, Pestka JJ (2008) Deoxynivalenol induces p38 interaction with the ribosome in monocytes and macrophages. Toxicol Sci 105(1):59–66
Bae EY, Lee SW, Seong S et al (2015) Inhibitory effects of verrucarin A on tunicamycin-induced ER stress in FaO rat liver cells. Molecules 20:8988–8996
Baltriukiene D, Kalvelyte A, Bukelskiene V (2007) Induction of apoptosis and activation of JNK and p38 MAPK pathways in deoxynivalenol-treated cell lines. Altern Lab Anim 35(1):53–59
Bennett JW, Klich M (2003) Mycotoxins. Clin Microbiol Rev 16(3):497–516
Bensassi F, El Golli-Bennour E, Abid-Essefi S et al (2009) Pathway of deoxynivalenol-induced apoptosis in human colon carcinoma cells. Toxicology 264(1–2):104–109
Bensassi F, Gallerne C, Sharaf El Dein O et al (2012) Involvement of mitochondria-mediated apoptosis in deoxynivalenol cytotoxicity. Food Chem Toxicol 50(5):1680–1689
Betina V (1989) Structure-activity relationships among mycotoxins. Chem Biol Interact 71:105–146
Bin-Umer MA, McLaughlin JE, Basu D et al (2011) Trichothecene mycotoxins inhibit mitochondrial translation-implication for the mechanism of toxicity. Toxins 3:1481–1501
Bin-Umer MA, McLaughlin JE, Butterly MS et al (2014) Elimination of damaged mitochondria through mitophagy reduces mitochondrial oxidative stress and increases tolerance to trichothecenes. PNAS 111(32):11798–11803
Black AP, Jones L, Malavige GN et al (2009) Immune evasion during varicella zoster virus infection of keratinocytes. Clin Exp Dermatol 34(8):941–944
Bondy GS, Pestka JJ (2000) Immunomodulation by fungal toxins. J Toxicol Env Heal B 3:109–143
Bouaziz C, Martel C, el Dein OS et al (2009) Fusarial toxin-induced toxicity in cultured cells and in isolated mitochondria involves PTPC-dependent activation of the mitochondrial pathway of apoptosis. Toxicol Sci 110(2):363–375
Boyle JP, Parkhouse R, Monie TP (2014) Insights into the molecular basis of the NOD2 signalling pathway. Open Biol 4(12):140178
Brigger I, Dubernet C, Couvreur P (2002) Nanoparticles in cancer therapy and diagnosis. Adv Drug Deliver Rev 54(5):631–651
Buckland J (2013) Rheumatoid arthritis: autophagy: a dual role in the life and death of RASFs. Nat Rev Rheumatol 9(11):637
Cadwell K (2016) Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis. Nat Rev Immunol 16(11):661–675
Cano PM, Seeboth J, Meurens F et al (2013) Deoxynivalenol as a new factor in the persistence of intestinal inflammatory diseases: an emerging hypothesis through possible modulation of Th17-mediated response. PLoS One 8(1):e53647
Choi BK, Jeong SH, Cho JH et al (2013) Effects of oral deoxynivalenol exposure on immune-related parameters in lymphoid organs and serum of mice vaccinated with porcine parvovirus vaccine. Mycotoxin Res 29:185–192
Choi YJ, Shin HW, Chun YS et al (2016) Diacetoxyscirpenol as a new anticancer agent to target hypoxia-inducible factor 1. Oncotarget 7(38):62107–62122
Chung YJ, Zhou HR, Pestka JJ (2003) Transcriptional and posttranscriptional roles for p38 mitogen-activated protein kinase in upregulation of TNF-α expression by deoxynivalenol (vomitoxin). Toxicol Appl Pharmacol 193(2):188–201
Clarke AJ, Ellinghaus U, Cortini A et al (2015) Autophagy is activated in systemic lupus erythematosus and required for plasmablast development. Ann Rheum Dis 74(5):912–920
Cooray R, Jonsson P (1990) Modulation of resistance to mastitis pathogens by pretreatment of mice with T-2 toxin. Food Chem Toxicol 28(10):687–692
Cooray R, Lindahl-Kiessling K (1987) Effect of T-2 toxin on the spontaneous antibody-secreting cells and other non-lymphoid cells in the murine spleen. Food Chem Toxicol 25(1):25–29
Corrier DE (1991) Mycotoxicosis: mechanisms of immunosuppression. Vet Immunol Immunopathol 30(1):73–87
Corrier DE, Ziprin RL (1986a) Enhanced resistance to listeriosis induced in mice by preinoculation treatment with T-2 mycotoxin. Am J Vet Res 47(4):856–859
Corrier DE, Ziprin RL (1986b) Immunotoxic effects of T-2 toxin on cell-mediated immunity to listeriosis in mice:comparison with cyclophosphamide. Am J Vet Res 47(9):1956–1960
Corrier DE, Ziprin RL, Mollenhauer HH (1987a) Modulation of cell-mediated resistance to listeriosis in mice given T-2 toxin. Toxicol Appl Pharmacol 89(3):323–331
Corrier DE, Holt PS, Mollenhauer HH (1987b) Regulation of murine macrophage phagocytosis of sheep erythrocytes by T-2 toxin. Am J Vet Res 8(8):1304–1307
Couper KN, Blount DG, Riley EM (2008) IL-10: the master regulator of immunity to infection. J Immunol 180:5771–5777
Cozzini P, Dellafiora L (2012) In silico approach to evaluate molecular interaction between mycotoxins and the estrogen receptors ligand binding domain: a case study on zearalenone and its metabolites. Toxicol Lett 214:81–85
Cundliffe E, Davies JE (1977) Inhibition of initiation, elongation, and termination of eukaryotic protein synthesis by trichothecene fungal toxins. Antimicrob Agents Ch 11:491–499
Dai Y, Hu S (2016) Recent insights into the role of autophagy in the pathogenesis of rheumatoid arthritis. Rheumatology 55(3):403–410
Das DN, Naik PP, Nayak A et al (2016) Bacopa monnieri-induced protective autophagy inhibits Benzo[a]pyrene-mediated apoptosis. Phytother Res 30(11):1794–1801
de Carvalho MP, Weich H, Abraham WR (2016) Macrocyclic trichothecenes as antifungal and anticancer compounds. Curr Med Chem 23(1):23–25
Deeb D, Gao X, Liu Y et al (2016) The inhibition of cell proliferation and induction of apoptosis in pancreatic ductal adenocarcinoma cells by verrucarin A, a macrocyclic trichothecene, is associated with the inhibition of Akt/NF-кB/mTOR prosurvival signaling. Int J Oncol 49:1139–1147
Dellafiora L, Galaverna G, Dall’Asta C (2017) In silico analysis sheds light on the structural basis underlying the ribotoxicity of trichothecenes—a tool for supporting the hazard identification process. Toxicol Lett 270:80–87
Deng Y, Wang Y, Zhang X et al (2017) Effects of T-2 toxin on pacific white shrimp litopenaeus vannamei: growth, and antioxidant defenses and capacity and histopathology in the hepatopancreas. J Aquat Anim Health 29:15–25
Desjardins AE, McCormick SP, Appell M (2007) Structure-activity relationships of trichothecene toxins in an Arabidopsis thaliana leaf assay. J Agric Food Chem 55(16):6487–6492
Diamond M, Reape TJ, Rocha O et al (2013) The Fusarium mycotoxin deoxynivalenol can inhibit plant apoptosis-like programmed cell death. PLoS One 8(7):e69542
Du RH, Cui JT, Wang T et al (2012) Trichothecin induces apoptosis of HepG2 cells via caspase-9 mediated activation of the mitochondrial death pathway. Toxicon 59:143–150
Fang H, Wu Y, Guo J et al (2012) T-2 toxin induces apoptosis in differentiated murine embryonic stem cells through reactive oxygen species-mediated mitochondrial pathway. Apoptosis 17(8):895–907
Fang H, Cong L, Zhi Y et al (2016) T-2 toxin inhibits murine ES cells cardiac differentiation and mitochondrial biogenesis by ROS and p-38 MAPK-mediated pathway. Toxicol Lett 258:259–266
Fimiani V, Richetti A (1993) Antitumor effect of a mycotoxin: rubratoxin B. Chemotherapy 39(1):59–62
Finocchiaro G (2017) TLRgeting evasion of immune pathways in Glioblastoma. Cell Stem Cell 20(4):422–424
Flannery BM, He K, Pestka JJ (2013) Deoxynivalenol-induced weight loss in the diet-induced obese mouse is reversible and PKR-independent. Toxicol Lett 221(1):9–14
Forsell JH, Pestka JJ (1985) Relation of 8-ketotrichothecene and zearalenone analog structure to inhibition of mitogen-induced human lymphocyte blastogenesis. Appl Environ Microbiol 50(5):1304–1307
Garreau de Loubresse N, Prokhorova I, Holtkamp W et al (2014) Structural basis for the inhibition of the eukaryotic ribosome. Nature 513:517–522
Gauthier T, Waché Y, Laffitte J et al (2013) Deoxynivalenol impairs the immune functions of neutrophils. Mol Nutr Food Res 57(6):1026–1036
Gojis O, Rudraraju B, Alifrangis C et al (2010) The role of steroid receptor coactivator-3 (SRC-3) in human malignant disease. EJSO 36(3):224–229
Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32(5):593–604
Gosselina E, Denisb O, Cauwenbergec AV et al (2012) Quantification of the trichothecene Verrucarin-A in environmental samples using an antibody-based spectroscopic biosensor. Sensor Actuat B 10:166–167
Gray JS, Bae HK, Li JC et al (2008) Double-stranded RNA-activated protein kinase mediates induction of interleukin-8 expression by deoxynivalenol, Shiga toxin 1, and ricin in monocytes. Toxicol Sci 105(2):322–330
Grove JF, Hosken M (1975) The larvicidal activity of some 12,13-epoxytrichothece-9-enes. Biochem Pharmacol 24:959–962
Gu W, Cui R, Ding T et al (2017) Simvastatin alleviates airway inflammation and remodelling through up-regulation of autophagy in mouse models of asthma. Respirology 22(3):533–541
Guerrero-Netro HM, Chorfi Y, Price CA (2015) Effects of the mycotoxin deoxynivalenol on steroidogenesis and apoptosis in granulosa cells. Reproduction 149(6):555–561
Han J, Wang T, Fu L et al (2015) Altered oxidative stress, apoptosis/autophagy, and epigenetic modifications in Zearalenone-treated porcine oocytes. Toxicol Res 4(5):1184–1194
Han J, Wang QC, Zhu CC et al (2016) Deoxynivalenol exposure induces autophagy/apoptosis and epigenetic modification changes during porcine oocyte maturation. Toxicol Appl Pharm 300:70–76
Hara KY, Sugita KY, Kasuga F et al (1996) Effects of deoxynivalenol on Salmonella enteritidis infection. Jsm Mycotoxins 42(42):51–55
Harris AL (2002) Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47
He K, Zhou HR, Pestka JJ (2012a) Targets and intracellular signaling mechanisms for deoxynivalenol-induced ribosomal RNA cleavage. Toxicol Sci 127(2):382–390
He ZJ, Zhu FY, Li SS et al (2017) Inhibiting ROS-NF-kappaB-dependent autophagy enhanced brazilin-induced apoptosis in head and neck squamous cell carcinoma. Food Chemical Toxicol 101:55–66
Hirano S, Kataoka T (2013) Deoxynivalenol induces ectodomain shedding of TNF receptor 1 and thereby inhibits the TNF-α-induced NF-κB signaling pathway. Eur J Pharmacol 701(1–3):144–151
Hou R, Jiang C, Zheng Q et al (2015) The AreA transcription factor mediates the regulation of deoxynivalenol (DON) synthesis by ammonium and cyclic adenosine monophosphate (cAMP) signalling in Fusarium graminearum. Molecul Plant Pathol 16(9):987–999
Hromas RA, Yung WK (1986) Anguidine potentiates cis-platinum in human brain tumor cells. J Neurooncol 3:343–348
Huang C, Zhang Q, Feng W (2015) Regulation and evasion of antiviral immune responses by porcine reproductive and respiratory syndrome virus. Virus Res 202:101–111
Hwang DW, So KS, Kim SC et al (2017) Autophagy induced by CX-4945, a casein kinase 2 inhibitor, enhances apoptosis in pancreatic cancer cell lines. Pancreas 46(4):575–581
Hymery N, Léon K, Carpentier FG et al (2009) T-2 toxin inhibits the differentiation of human monocytes into dendritic cells and macrophages. Toxicol in Vitro 23:509–519
Iida A, Konishi K, Kubo H et al (1996) Trichothecinols A, B and C, potent anti-tumor promoting sesquiterpenoids from the fungus Trichothecium roseum. Tetrahedron Lett 37(51):9219–9220
Ikawa M, Carr C, Tatsuno T (1985) Trichothecene structure and toxicity to the green alga Chlorella pyrenoidosa. Toxicon 23(3):535–537
Islam Z, Nagase M, Yoshizawa T et al (1988) T-2 toxin induces thymic apoptosis in vivo in mice. Toxicol Appl Pharmacol 148(2):205–214
Islam Z, Gray JS, Pestka JJ (2006) p38 Mitogen-activated protein kinase mediates IL-8 induction by the ribotoxin deoxynivalenol in human monocytes. Toxicol Appl Pharmacol 213(3):235–244
Islam MR, Roh YS, Kim J et al (2013) Differential immune modulation by deoxynivalenol (vomitoxin) in mice. Toxicol Lett 221(2):152–163
Ito Y, Yanase S, Fujita J et al (1981) A short-term in vitro assay for promoter substances using human lymphoblastoid cells latently infected with Epstein-Barr virus. Cancer Lett 13(1):29–37
Jarvis BB, Stahly GP, Curtis CR (1978) Antitumor activity of fungal metabolites: verrucarin beta-9, 10-epoxides. Cancer Treatment Rep 62(10):1585–1586
Jarvis BB, Stahly GP, Pavanasasivam G et al (1980) Antileukemic compounds derived from the chemical modification of macrocyclic trichothecenes. 1. Derivatives of verrucarin A. J Med Chem 23(9):1054–1058
Jarvis BB, Eppley RM, Mazolla EP (1983) Chemistry and bioproduction of macrocyclic trichothecenes. In: Ueno Y (ed) Trichothecenes—chemical, biological and toxicological aspects. Elsevier, Amsterdam, pp 20–38
Jarvis BB, Midiwo JO, Mazzola EP (1984) Antileukemic compounds derived by chemical modification of macrocyclic trichothecenes. 2. Derivatives of roridins A and H and verrucarins A and J. J Med Chem 27(2):239–244
Jayasooriya RG, Moon DO, Park SR et al (2013a) Combined treatment with verrucarin A and tumor necrosis factor-α sensitizes apoptosis by overexpression of nuclear factor-kappaB-mediated Fas. Environ Toxicol Pharmacol 36(2):303–310
Jayasooriya RG, Moon DO, Yun SG et al (2013b) Verrucarin A enhances TRAIL-induced apoptosis via NF-κB-mediated Fas overexpression. Food Chem Toxicol 55:1–7
Jeker N, Tamm C (1988) Synthesis of new unnatural macrocyclic trichothecenes: 4-epiverrucarin A. Helv Chim Acta 1:1904
Jia Q, Zhou HR, Shi Y et al (2006) Docosahexaenoic acid consumption inhibits deoxynivalenol-induced CREB/ATF1 activation and IL-6 gene transcription in mouse macrophages. J Nutr 136(2):366–372
Jun DY, Kim JS, Park HS et al (2007) Cytotoxicity of diacetoxyscirpenol is associated with apoptosis by activation of caspase-8 and interruption of cell cycle progression by down-regulation of cdk4 and cyclin B1 in human Jurkat T cells. Toxicol Appl Pharmacol 15:190–201
Kanai K, Kondo E (1984) Decreased resistance to mycobacterial infection in mice fed a trichothecene compound (T-2 toxin). Japan J Med Sci Biol 37(2):97–104
Karlovsky P (2011) Biological detoxification of the mycotoxin deoxynivalenol and its use in genetically engineered crops and feed additives. Appl Microbiol Biotechnol 91:491–504
Katika MR, Hendriksen PJ, van Loveren H et al (2015) Characterization of the modes of action of deoxynivalenol (DON) in the human Jurkat T-cell line. J Immunotoxicol 12(3):206–216
Ke PY (2017) Horning cell self-digestion: autophagy wins the 2016 Nobel Prize in physiology or medicine. Biomed J 40(1):5–8
Ke Q, Costa M (2006) Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol 70(5):1469–1480
Kim HS, Lee MS (2007) STAT1 as a key modulator of cell death. Cell Signal 19:454–465
Kim EY, Moudgil KD (2017) Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines. Cytokine 98:87–96
Kojima S, Nakamura N, Ueno Y et al (1993) Anti-tumor activity of T-2 Toxin-conjugated A7 monoclonal antibody (T-2-A7 MoAb) against human colon carcinoma. Nat Toxins 1:209–215
Königs M, Schwerdt G, Gekle M et al (2008) Effects of the mycotoxin deoxynivalenol on human primary hepatocytes. Mol Nutr Food Res 2(7):830–839
Konishi K, Iida A, Kaneko M et al (2003) Cancer preventive potential of trichothecenes from Trichothecium roseum. Bioorg Med Chem 1:2511–2518
Kubena LF, Bailey RH, Byrd JA et al (2001) Cecal volatile fatty acids and broiler chick susceptibility to Salmonella typhimurium colonization as affected by aflatoxins and T-2 toxin. Poult Sci 80(4):411–417
Kubo M, Motomura Y (2012) Transcriptional regulation of the anti-inflammatory cytokine IL-10 in acquirec immune cells. Front Immuno 3:275
Kugler KG, Jandric Z, Beyer R et al (2016) Ribosome quality control is a central protection mechanism for yeast exposed to deoxynivalenol and trichothecin. BMC Genomics 17:417
Kwon O, Soung NK, Thimmegowda NR et al (2012) Patulin induces colorectal cancer cells apoptosis through EGR-1 dependent ATF3 up-regulation. Cell Signal 24(4):943–950
LaRock CN, Nizet V (2015) Inflammasome/IL-1 beta responses to streptococcal pathogens. Front Immuno 6:518
Lee KH, Nishimura S, Matsunaga S et al (2006) Induction of a ribotoxic stress response that stimulates stress-activated protein kinases by 13-deoxytedanolide, an antitumor marine macrolide. Biosci Biotechnol Biochem 70(1):161–171
Lessard M, Savard C, Deschene K et al (2015) Impact of deoxynivalenol (DON) contaminated feed on intestinal integrity and immune response in swine. Food Chem Toxicol 80:7–16
Li M, Cuff CF, Pestka J (2005) Modulation of murine host response to enteric reovirus infection by the trichothecene deoxynivalenol. Toxicol Sci 87(1):134–145
Li M, Cuff CF, Pestka JJ (2006a) T-2 toxin impairment of enteric reovirus clearance in the mouse associated with suppressed immunoglobulin and IFN-γ responses. Toxic Appl Pharmacol 214:318–325
Li M, Harkema JR, Islam Z et al (2006b) T-2 toxin impairs murine immune response to respiratory reovirus and exacerbates viral bronchiolitis. Toxic Appl Pharmacol 7:76–85
Li SJ, Pasmans F, Croubels S et al (2013) T-2 toxin impairs antifungal activities of chicken macrophages against Aspergillus fumigatus conidia but promotes the pro-inflammatory responses. Avian Pathol 42(5):457–463
Li D, Ma H, Ye Y et al (2014) Deoxynivalenol induces apoptosis in mouse thymic epithelial cells through mitochondria-mediated pathway. Environ Toxicol Pharmacol 38(1):163–171
Li DY, Han J, Guo X et al (2016) The effects of T-2 toxin on the prevalence and development of Kashin-Beck disease in China:a meta-analysis and systematic review. Toxicology Res 5(3):731–751
Li B, Lu M, Jiang XX et al (2017) Inhibiting reactive oxygen species-dependent autophagy enhanced baicalein-induced apoptosis in oral squamous cell carcinoma. J Nat Med 71(2):433–441
Liu J, Wang L, Guo X et al (2014a) The role of mitochondria in T-2 toxin-induced human chondrocytes apoptosis. PLoS One 9(9):e108394
Liu J, Simmons SO, Pei R (2014b) Regulation of IL-8 promoter activity by verrucarin A in human monocytic THP-1 cells. J Toxicol Environ Health A 77(19):1125–1140
Liu YN, Wang YX, Liu XF et al (2015) Citreoviridin induces ROS-dependent autophagic cell death in human liver HepG2 cells. Toxicon 95:30–37
Liu Y, Gao X, Deeb D et al (2016) Mycotoxin verrucarin A inhibits proliferation and induces apoptosis in prostate cancer cells by inhibiting prosurvival Akt/NF-kB/mTOR signaling. J Exp Ther Oncol 11(4):251–260
Liu X, Guo P, Liu A et al (2017a) Nitric oxide (NO)-mediated mitochondrial damage plays a critical role in T-2 toxin-induced apoptosis and growth hormone deficiency in rat anterior pituitary GH3 cells. Food Chem Toxicol 102:11–23
Liu X, Huang D, Guo P et al (2017b) PKA/CREB and NF-κB pathway regulates AKNA transcription: A novel insight into T-2 toxin-induced inflammation and GH deficiency in GH3 cells. Toxicology 392:81–95
Lucioli J, Pinton P, Callu P et al (2013) The food contaminant deoxynivalenol activates the mitogen activated protein kinases in the intestine:Interest of ex vivo models as an alternative to in vivo experiments. Toxicon 66:31–36
Lum JJ, DeBerardinis RJ, Thompson CB (2005) Autophagy in metazoans:cell survival in the land of plenty. Nature Rev Mol Cell Biol 6:439–448
Ma YN, Zhang AH, Shi ZY et al (2012) A mitochondria-mediated apoptotic pathway induced by deoxynivalenol in human colon cancer cells. Toxicol in Vitro 26:414–420
Madhyastha MS, Marquardt RR, Abramson D (1994) Structure-activity relationships and interactions among trichothecene mycotoxins as assessed by yeast bioassay. Toxicon 32(9):1147–1152
Mahmuda A, Bande F, Al-Zihiry KJK et al (2017) Monoclonal antibodies: a review of therapeutic applications and future prospects. Trop J Pharm Res 16(3):713–722
Maiuri C, Zalckvar E, Kimchi A et al (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nature Rev Mol Cell Biol 8:741–752
Marzocco S, Russo R, Bianco G et al (2009) Pro-apoptotic effects of nivalenol and deoxynivalenol trichothecenes in J774A.1 murine macrophages. Toxicol Lett 89(1):21–26
Mbandi E, Pestka JJ (2006) Deoxynivalenol and satratoxin G potentiate proinflammatory cytokine and macrophage inhibitory protein 2 induction by Listeria and Salmonella in the macrophage. J Food Prot 69(6):1334–1339
McCormick SP, Stanley AM, Stover NA et al (2011) Trichothecenes: from simple to complex mycotoxins. Toxins (Basel) 3(7):802–814
Melero I, Hervas-Stubbs S, Glennie M et al (2007) Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer 7(2):95–106
Messer JS (2017) The cellular autophagy/apoptosis checkpoint during inflammation. Cell Mol Life Sci 74(7):1281–1296
Mikami O, Yamaguchi H, Murata H et al (2010) Induction of apoptotic lesions in liver and lymphoid tissues and modulation of cytokine mRNA expression by acute exposure to deoxynivalenol in piglets. J Vet Sci 11(2):107–113
Miller K, Atkinson HA (1986) The in vitro effects of trichothecenes on the immune system. Food Chem Toxicol 24(6–7):545–549
Mishra S, Tripathi A, Chaudhari BP et al (2014) Deoxynivalenol induced mouse skin cell proliferation and inflammation via MAPK pathway. Toxicol Appl Pharmacol 279(2):186–197
Moon Y, Pestka JJ (2002) Vomitoxin-induced cyclooxygenase-2 gene expression in macrophages mediated by activation of ERK and p38 but not JNK mitogen-activation protein kinases. Toxicol Sci 69:373–382
Moon DO, Asami Y, Long H et al (2013) Verrucarin A sensitizes TRAIL-induced apoptosis via the upregulation of DR5 in an eIF2α/CHOP-dependent manner. Toxicol In Vitro 27(1):257–263
Mu P, Xu M, Zhang L et al (2013) Proteomic changes in chicken primary hepatocytes exposed to T-2 toxin are associated with oxidative stress and mitochondrial enhancement. Proteomics 13(21):3175–3188
Muenst S, Läubli H, Soysal SD et al (2016) The immune system and cancer evasion strategies: therapeutic concepts. J Intern Med 79(6):541–562
Murakami Y, Okuda T, Shindo K et al (2001) New macrocyclic trichothecene group antitumor antibiotics, from Myrothecium verrucaria. J Antibiot 54(11):980–983
Nagar R (2017) Autophagy: a brief overview in perspective of dermatology. Indian J Dermatol Venereol Leprol 83(3):290–297
Nawrocki ST, Carew JS, Dunner, KJr et al (2005) Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. Cancer Res 65(24):11510–11519
Nelsen CJ, Murtaugh MP, Faaberg KS (1999) Porcine reproductive and respiratory syndrome virus comparison:divergent evolution on two continents. J Virol 73(1):270–280
Neumann EJ, Kliebenstein JB, Johnson CD et al (2005) Assessment of the economic impact of porcine reproductive and respiratory syndrome on swine production in the United States. J Am Vet Med Assoc 227(3):385–392
Ngampongsa S, Hanafusa M, Ando K et al (2013) Toxic effects of T-2 toxin and deoxynivalenol on the mitochondrial electron transport system of cardiomyocytes in rats. J Toxicol Sci 38(3):495–502
Nibert ML, Margraf RL, Coombs KM (1996) Nonrandom segregation of parental alleles in reovirus reassortants. J Virol 70(10):7295–7300
Oda T, Xu J, Ukai K et al (2010) 12′-Hydroxyl group remarkably reduces Roridin E cytotoxicity. Mycoscience 51:317–320
Oeckinghaus A, Hayden MS, Ghosh S (2011) Crosstalk in NF-kappa B signaling pathways. Nat Immunol 12(8):695–708
Ohtani K, Murakami H, Shibuya O et al (1990) Antitumor activity of T-2 toxin-conjugated monoclonal antibody to murine thymoma. Japan J Exp Med 60(2):57–65
Opriessnig T, Meng XJ, Halbur PG (2007) Porcine circovirus type 2 associated disease: update on current terminology, clinical manifestations, pathogenesis, diagnosis, and intervention strategies. J Vet Diagn Invest 19(6):591–615
Orvedahl A, Macpherson S Jr RS et al (2010) Autophagy protects against sindbis virus infection of the central nervous system. Cell Host Microbe 7(2):115–127
Pace JG, Watts MR, Canterbury WJ (1988) T-2 mycotoxin inhibits mitochondrial protein synthesis. Toxicon 26:77–85
Pai RK, Convery M, Hamilton TA et al (2003) Inhibition of IFN-gamma-induced class II transactivator expression by a 19-kDa lipoprotein from Mycobacterium tuberculosis: a potential mechanism for immune evasion. J Immunol 171(1):175–184
Palanivel K, Kanimozhi V, Kadalmani B et al (2013) Verrucarin A, a protein synthesis inhibitor, induces growth inhibition and apoptosis in breast cancer cell lines MDA-MB-231 and T47D. Biotechnol Lett 35(9):1395–1403
Palanivel K, Kanimozhi V, Kadalmani B (2014a) Verrucarin A alters cell-cycle regulatory proteins and induces apoptosis through reactive oxygen species-dependent p38MAPK activation in the human breast cancer cell line MCF-7. Tumour Biol 35(10):10159–10167
Palanivel K, Kanimozhi V, Kadalmani B et al (2014b) Verrucarin A induces apoptosis through ROS-mediated EGFR/MAPK/Akt signaling pathways in MDA-MB-231 breast cancer cells. J Cell Biochem 115(11):2022–2032
Pan X, Whitten DA, Wu M et al (2013a) Global protein phosphorylation dynamics during deoxynivalenol-induced ribotoxic stress response in the macrophage. Toxicol Appl Pharmacol 268(2):201–211
Pan X, Whitten DA, Wu M et al (2013b) Early phosphoproteomic changes in the mouse spleen during deoxynivalenol-induced ribotoxic stress. Toxicol Sci 135(1):129–143
Pan X, Whitten DA, Wilkerson CG et al (2014) Dynamic changes in ribosome-associated proteome and phosphoproteome during deoxynivalenol-induced translation inhibition and ribotoxic stress. Toxicol Sci 138(1):217–233
Parker BS, Slaney CY, Bidwell BN et al (2011) Tumor cell induced immune evasion via loss of Type I IFN signalling promotes breast cancer metastasis. Cytokine 56:102
Payros D, Alassane-Kpembi I, Pierron A et al (2016) Toxicology of deoxynivalenol and its acetylated and modified forms. Arch Toxicol 90(12):2931–2957
Pestka JJ (2003) Deoxynivalenol-induced IgA production and IgA nephropathy-aberrant mucosal immune response with systemic repercussions. Toxicol Lett 140:287–295
Pestka JJ (2010) Deoxynivalenol: mechanisms of action, human exposure, and toxicological relevance. Arch Toxicol 4(9):663–679
Pestka JJ, Tai JH, Wlrr MF et al (1987) Suppression of immune response in the b6c3fi mouse after dietary exposure to the Fusarium mycotoxins deoxynivalenol (vomitoxin) and zearalenone. Food Chem Toxic 25(4):297–304
Pestka JJ, Yan D, King LE (1994) Flow cytometric analysis of the effects of in vitro exposure to vomitoxin (deoxynivalenol) on apoptosis in murine T, B and IgA+ cells. Food Chem Toxicol 32(12):1125–1136
Pestka JJ, Zhou HR, Moon Y et al (2004) Cellular and molecular mechanisms for immune modulation by deoxynivalenol and other trichothecenes: unraveling a paradox. Toxicol Lett 153(1):61–73
Pham DL, Ban GY, Kim SH et al (2017) Neutrophil autophagy and extracellular DNA traps contribute to airway inflammation in severe asthma. Clin Exp Allergy 47(1):57–70
Pierdominici M, Vomero M, Barbati C et al (2012) Role of autophagy in immunity and autoimmunity, with a special focus on systemic lupus erythematosus. FASEB J 26(4):1400–1412
Pierron A, Mimoun S, Murate LS et al (2016) Microbial biotransformation of DON: molecular basis for reduced toxicity. Sci Rep 6:29105
Pietsch C, Katzenback BA, Garcia-Garcia E et al (2015) Acute and subchronic effects on immune responses of carp (Cyprinus carpio L.) after exposure to deoxynivalenol (DON) in feed. Mycotoxin Res 31(3):151–164
Pinton P, Oswald IP (2014) Effect of deoxynivalenol and other Type B trichothecenes on the intestine: a review. Toxins (Basel) 6(5):1615–1643
Pinton P, Accensi F, Beauchamp E et al (2008) Ingestion of deoxynivalenol (DON) contaminated feed alters the pig vaccinal immune responses. Toxicol Lett 177(3):215–222
Pinton P, Braicu C, Nougayrede JP et al (2010) Deoxynivalenol impairs porcine intestinal barrier function and decreases the protein expression of claudin-4 through a mitogen-acitivated protein kinase-dependent mechanism. J Nutr 140:1956–1962
Pinton P, Tsybulskyy D, Lucioli J et al (2012) Toxicity of deoxynivalenol and its acetylated derivatives on the intestine: differential effects on morphology, barrier function, tight junction proteins, and mitogen-activated protein kinases. Toxicol Sci 130(1):180–190
Pinton P, Graziani F, Pujol A et al (2015) Deoxynivalenol inhibits the expression by goblet cells of intestinal mucins through a PKR and MAP kinase dependent repression of the resistin-like molecule β. Mol Nutr Food Res 59(6):1076–1087
Reinhart D, Kunert R (2015) Upstream and downstream processing of recombinant IgA. Biotechnol Lett 37(2):241–251
Ren Z, Wang Y, Deng H et al (2015) Deoxynivalenol-induced cytokines and related genes in concanavalin A-stimulated primary chicken splenic lymphocytes. Toxicol in Vitro 29(3):558–563
Rogers LM, Veeramani S, Weiner GJ (2014) Complement in monoclonal antibody therapy of cancer. Immunol Res 59(1–3):203–210
Roh HJ, Sung HW, Kwon HM (2006) Effects of DDA, CpG-ODN, and plasmid-encoded chicken IFN-gamma on protective immunity by a DNA vaccine against IBDV in chickens. J Vet Sci 7(4):361–368
Ryan HE, Poloni M, McNulty W et al (2000) Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. Cancer Res 60(15):4010–4015
Ryu SM, Lee HM, Song EG et al (2017) Antiviral activities of trichothecenes isolated from Trichoderma albolutescens against Pepper Mottle Virus. J Agric Food Chem 65(21):4273–4279
Salceda S, Caro J (1997) Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 272(36):22642–22647
Salem M, Ammitzboell M, Nys K et al (2015) ATG16L1: a multifunctional susceptibility factor in Crohn disease. Autophagy 11(4):585–594
Salem IB, Boussabbeh M, Da Silva JP et al (2017) SIRT1 protects cardiac cells against apoptosis induced by zearalenone or its metabolites alpha- and beta-zearalenol through an autophagy-dependent pathway. Toxicol Appl Pharm 314:82–90
Samrat SK, Vedi S, Singh S et al (2015) Immunization with recombinant adenoviral vectors expressing HCV core or F proteins leads to T cells with reduced effector molecules granzyme B and IFN-γ: a potential new strategy for immune evasion in HCV infection. Viral Immunol 28(6):309–324
Savard C, Pinilla V, Provost C et al (2014a) In vivo effect of deoxynivalenol (DON) naturally contaminated feed on porcine reproductive and respiratory syndrome virus (PRRSV) infection. Vet Microbiol 174(3–4):419–426
Savard C, Pinilla V, Provost C et al (2014b) In vitro effect of deoxynivalenol (DON) mycotoxin on porcine reproductive and respiratory syndrome virus replication. Food Chem Toxicol 65:219–226
Savard C, Gagnona CA, Chorfi Y (2015a) Deoxynivalenol (DON) naturally contaminated feed impairs theimmune response induced by porcine reproductive and respiratorysyndrome virus (PRRSV) live attenuated vaccine. Vaccine 33:3881–3886
Savard C, Provost C, Alvarez F et al (2015b) Effect of deoxynivalenol (DON) mycotoxin on in vivo and in vitro porcine circovirus type 2 infections. Vet Microbiol 176(3–4):257–267
Seeboth J, Solinhac R, Oswald IP et al (2012) The fungal T-2 toxin alters the activation of primary macrophages induced by TLR-agonists resulting in a decrease of the inflammatory response in the pig. Vet Res 43:35
Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncongene 29(5):625–634
Sergent T, Parys M, Garsou S et al (2006) Deoxynivalenol transport across human intestinal Caco-2 cells and its effects on cellular metabolism at realistic intestinal concentrations. Toxicol Lett 164(2):167–176
Shi Y, Pestka JJ (2009) Mechanisms for suppression of interleukin-6 expression in peritoneal macrophages from docosahexaenoic acid-fed mice. J Nutr Biochem 20(5):358–368
Shi Y, Porter K, Parameswaran N et al (2009) Role of GRP78/BiP degradation and ER stress in deoxynivalenol-induced interleukin-6 upregulation in the macrophage. Toxicol Sci 109(2):247–255
Shifrin VI, Anderson P (1999) Trichothecene mycotoxins trigger a ribotoxic stress response that activates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase and induces apoptosis. J Biol Chem 274(20):13985–13992
Smitka TA, Bunge RH, Bloem RJ et al (1984) Two new trichothecenes, PD 113,325 and PD 113,326. J Antibiot (Tokyo) 37(8):823–828
Solhaug A, Torgersen ML, Holme JA et al (2014) Autophagy and senescence, stress responses induced by the DNA-damaging mycotoxin alternariol. Toxicology 326:119–129
Srivastava KD, Rom WJ, Yie TA et al (2002) Crucial role of interleukin-1beta and nitricoxide synthase in silica-induced inflammation and apoptosis in mice. Am J Respir Crit Care Med 165:527–533
Steinmetz WE, Rodarte CB, Lin A (2009) 3D QSAR study of the toxicity of trichothecene mycotoxins. Eur J Med Chem 44(11):4485–4489
Stephanou A, Latchman DS (2005) Opposing actions of STAT-1 and STAT-3. Growth Factors 23:177–182
Su J, Zhao P, Kong L et al (2013) Trichothecin induces cell death in NF-κB constitutively activated human cancer cells via inhibition of IKK phosphorylation. PLoS One 8(8):e71333
Sugita-Konishi Y, Hara-Kudo Y, Kasuga F et al (1988) The effects of trichothecenes on host defense against infectious diseases. Mycotoxins 47:19–23
Sugiyama K, Muroi M, Tanamoto K et al (2010) Deoxynivalenol and nivalenol inhibit lipopolysaccharide-induced nitric oxide production by mouse macrophage cells. Toxicol Lett 192(2):150–154
Sugiyama K, Muroi M, Kinoshita M et al (2016) NF-κB activation via MyD88-dependent Toll-like receptor signaling is inhibited by trichothecene mycotoxin deoxynivalenol. J Toxicol Sci 41(2):273–279
Tai JH, Pestka JJ (1988) Impaired murine resistance to Salmonella typhimurium following oral exposure to the trichothecene T-2 toxin. Food Chem Toxicol 26(8):691–698
Tai JH, Pestka JJ (1990) T-2 toxin impairment of murine response to Salmonella typhimurium: a histopathologic assessment. Mycopathologia 109(3):149–155
Tang Y, Li J, Li F et al (2015) Autophagy protects intestinal epithelial cells against deoxynivalenol toxicity by alleviating oxidative stress via IKK signaling pathway. Free Radical Bio Med 89:944–951
Thomson BJ (2001) Viruses and apoptosis. Int J Exp Pathol 82:65–76
Tian J, Yan J, Wang W et al (2012) T-2 toxin enhances catabolic activity of hypertrophic chondrocytes through ROS-NF-κB-HIF-2α pathway. Toxicol in Vitro 26(7):1106–1113
Tien JC, Xu J (2012) Steroid receptor coactivator-3 as a potential molecular target for cancer therapy. Expert Opin Ther Targets 16(11):1085–1096
Tominaga M, Momonaka Y, Yokose C et al (2016) Anorexic action of deoxynivalenol in hypothalamus and intestine. Toxicon 118:54–60
Turkmen K (2017) Inflammation, oxidative stress, apoptosis, and autophagy in diabetes mellitus and diabetic kidney disease: the four Horsemen of the apocalypse. Int Urol Nephrol 49(5):837–844
Ueno Y (1985) The toxicology of mycotoxins. Crit Rev Toxicol 14:99–132
Uzarski RL, Islam Z, Pestka JJ (2003) Potentiation of trichotheceneinduced leukocyte cytotoxicity and apoptosis by TNF-α and Fas activation. Chem Biol Interact 146:105–119
Van De Walle J, Romier B, Larondelle Y et al (2008) Influence of deoxynivalenol on NF-κB activation and IL-8 secretion in human intestinal Caco-2 cells. Toxicol Lett 177(3):205–214
Vandenbroucke V, Croubels S, Verbrugghe E et al (2009) The mycotoxin deoxynivalenol promotes uptake of Salmonella typhimurium in porcine macrophages, associated with ERK1/2 induced cytoskeleton reorganization. Vet Res 40(6):64
Vandenbroucke V, Croubels S, Martel A et al (2011) The mycotoxin deoxynivalenol potentiates intestinal inflammation by Salmonella typhimurium in porcine ileal loops. PLoS One 6(8):e23871
Verbrugghe E, Croubels S, Vandenbroucke V et al (2011) T-2 toxin alters host-pathogen interactions of Salmonella Typhimurium in pigs. In: 33rd Mycotoxin Workshop
Verbrugghe E, Croubels S, Vandenbroucke V, Goossens J et al (2012a) A modified glucomannan mycotoxin-adsorbing agent counteracts the reduced weight gain and diminishes cecal colonization of Salmonella Typhimurium in T-2 toxin exposed pigs. Res Vet Sci 93(3):1139–1141
Verbrugghe E, Vandenbroucke V, Dhaenens M et al (2012b) T-2 toxin induced Salmonella typhimurium intoxication results in decreased Salmonella numbers in the cecum contents of pigs, despite marked effects on Salmonella-host cell interactio. Vet Res 43:22
Vidal D, Mavet S (1989) In vitro and in vivo toxicity of T-2 toxin, a Fusarium mycotoxin, to mouse peritoneal macrophages. Infect Immun 57(7):2260–2264
Vu HL, Kwon B, Yoon KJ et al (2011) Immune evasion of porcine reproductive and respiratory syndrome virus through glycan shielding involves both glycoprotein 5 as well as glycoprotein 3. J Virol 85(11):5555–5564
Wan D, Wang X, Wu Q et al (2015) Integrated transcriptional and proteomic analysis of growth hormone suppression mediated by trichothecene T-2 toxin in rat GH3 cells. Toxicol Sci 147(2):326–338
Wang X, Liu Q, Ihsan A et al (2012) JAK/STAT pathway plays a critical role in the proinflammatory gene expression and apoptosis of RAW264.7 cells induced by trichothecenes as DON and T-2 toxin. Toxicol Sci 127(2):412–424
Wang Z, Wu Q, Kuča K et al (2014) Deoxynivalenol: signaling pathways and human exposure risk assessment—an update. Arch Toxicol 88(11):1915–1928
Wang YX, Liu YN, Liu XF et al (2015) Citreoviridin induces autophagy-dependent apoptosis through lysosomal-mitochondrial axis in human liver HepG2 cells. Toxins 7(8):3030–3044
Wang X, Wang Y, Qiu M et al (2017) Cytotoxicity of T-2 and modified T-2 toxins: induction of JAK/STAT pathway in RAW264. 7 cells by hepatopancreas and muscle extracts of shrimp fed T-2 toxin. Toxicol Res 6:144–151
Wannenmacher RW, Wiener SL (1997) Trichothecene mycotoxins. In: Sidell FR, Takafuji ET, Franz DR (eds) Medical aspects of chemical and biological warfare. Office of the Surgeon General at TMM Publications, Washington, DC, USA, pp 655–676
Wei CM, McLaughlin CS (1974) Structure-function relationship in the 12, 13-expoxytrichothecenes-Novel inhibitors of protein synthesis. Biochem Bioph Res Co 57(3):838–844
Wei S, van der Lee T, Verstappen E et al (2017) Targeting trichothecene biosynthetic genes. Methods Mol Biol 1542:173–189
Weidle UH, Tiefenthaler G, Schiller C et al (2014) Prospects of bacterial and plant protein-based immunotoxins for treatment of cancer. Cancer Genom Proteom 11(1):25–38
Wildenberg ME, Koelink PJ, Diederen K et al (2017) The ATG16L1 risk allele associated with Crohn’s disease results in a Rac1-dependent defect in dendritic cell migration that is corrected by thiopurines. Mucosal immunol 10(2):352–360
Woldemichael GM, Turbyville TJ, Vasselli JR et al (2012) Lack of a functional VHL gene product sensitizes renal cell carcinoma cells to the apoptotic effects of the protein synthesis inhibitor verrucarin A. Neoplasia 14(8):771–777
Won SJ, Yen CH, Liu HS et al (2015) Justicidin A-induced autophagy flux enhances apoptosis of human colorectal cancer cells via class III PI3K and Atg5 pathway. J Cell Physiol 230(4):930–946
Wu AM, Senter PD (2005) Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol 23(9):1137–1146
Wu X, Kohut M, Cunnick J et al (2009) Deoxynivalenol suppresses circulating and splenic leukocyte subpopulations in BALB/c mice: dose response, time course and sex differences. Food Addit Contam A 26(7):1070–1080
Wu Q, Vlastimil D, Huang L et al (2010) Metabolic pathways of trichothecenes. Drug Metab Rev 42(2):250–267
Wu Q, Huang L, Liu Z et al (2011) A comparison of hepatic in vitro metabolism of T-2 toxin in rats, pigs, chickens, and carp. Xenobiotica 41(10):863–873
Wu Q, Dohnal V, Kuca K et al (2013) Trichothecenes: structure-toxic activity relationships. Curr Drug Metab 14:641–660
Wu QH, Wang X, Yang W et al (2014a) Oxidative stress-mediated cytotoxicity and metabolism of T-2 toxin and deoxynivalenol in animals and humans: an update. Arch Toxicol 88(7):1309–1326
Wu Q, Wang X, Wan D et al (2014b) Crosstalk of JNK1-STAT3 is critical for RAW264.7 cell survival. Cell Signal 26:2951–2960
Wu J, Tu D, Yuan LY et al (2015) T-2 toxin regulates steroid hormone secretion of rat ovarian granulosa cells through cAMP-PKA pathway. Toxicol Lett 232:573–579
Wu W, Zhou HR, Pestka JJ (2017) Potential roles for calcium-sensing receptor (CaSR) and transient receptor potential ankyrin-1 (TRPA1) in murine anorectic response to deoxynivalenol (vomitoxin). Arch Toxicol 91(1):495–507
Xu J, Jiang C, Zhu W et al (2015) NOD2 pathway via RIPK2 and TBK1 is involved in the aberrant catabolism induced by T-2 toxin in chondrocytes. Osteoarthr Cartil 23(9):1575–1585
Yan F, Yu Y, Chow DC et al (2014) Identification of verrucarin a as a potent and selective steroid receptor coactivator-3 small molecule inhibitor. PLoS One 9(4):e95243
Yang GH, Jarvis BB, Chung YJ et al (2000) Apoptosis induction by the satratoxins and other trichothecene mycotoxins: relationship to ERK, p38 MAPK, and SAPK/JNK activation. Toxicol Appl Pharmacol 164(2):149–160
Yang L, Meng HZ, Yang M (2016) Autophagy protects osteoblasts from AGEs induced apoptosis through intracellular ROS. J Mol Endocrinol 56(4):291–300
Yin S, Guo X, Li J et al (2016) Fumonisin B1 induces autophagic cell death via activation of ERN1‑MAPK8/9/10 pathway in monkey kidney MARC‑145 cells. Arch Toxicol 90:985–996
Ying H, Willingham MC, Cheng SY (2008) The steroid receptor coactivator-3 is a tumor promoter in a mouse model of thyroid cancer. Oncogene 27(6):823–830
York B, O’Malley BW (2010) Steroid receptor coactivator (SRC) family: masters of systems biology. J Biol Chem 285(50):38743–38750
Zhang L, Fang B (2005) Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther 12:228–237
Zhang Q, Yoo D (2016) Immune evasion of porcine enteric coronaviruses and viral modulation of antiviral innate signaling. Virus Res 226:128–141
Zhang Y, Zhang B (2008) TRAIL resistance of breast cancer cells is associated with constitutive endocytosis of death receptors 4 and 5. Mol Cancer Res 6:1861–1871
Zhang J, Yang PL, Gray NS (2009) Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9(1):28–39
Zhang Y, Han J, Zhu CC et al (2016a) Exposure to HT-2 toxin causes oxidative stress induced apoptosis/autophagy in porcine oocytes. Sci Rep 6:33904
Zhang ZQ, Wang SB, Wang RG et al (2016b) Phosphoproteome analysis reveals the molecular mechanisms underlying deoxynivalenol-induced intestinal toxicity in IPEC-J2 cells. Toxins 8(10):270
Zhou HR, Islam Z, Pestka JJ (2003a) Rapid, sequential activation of mitogen-activated protein kinases and transcription factors precedes proinflammatory cytokine mRNA expression in spleens of mice exposed to the trichothecene vomitoxin. Toxicol Sci 72(1):130–142
Zhou HR, Lau AS, Pestka JJ (2003b) Role of double-stranded RNA-activated protein kinase R (PKR) in deoxynivalenol-induced ribotoxic stress response. Toxicol Sci 74:335–344
Zhou HR, Islam Z, Pestka JJ (2005a) Induction of competing apoptotic and survival signaling pathways in the macrophage by the ribotoixc trichothecene deoxynivalenol. Toxicol Sci 87(1):113–122
Zhou HR, Jia Q, Pestka JJ (2005b) Ribotoxic stress response to the trichothecene deoxynivalenol in the macrophage involves the SRC family kinase Hck. Toxicol Sci 85:916–926
Zhou HR, He K, Landgraf J et al (2014) 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. Toxins 6:3406–3425
Ziprin RL, Elissalde MH (1990) Effect of T-2 toxin on resistance to systemic Salmonella typhimurium infection of newly hatched chickens. Am J Vet Res 51(11):1869–1872
Ziprin RL, McMurray DN (1988) Differential effect of T-2 toxin on murine host resistance to three facultative intracellular bacterial pathogens: listeria monocytogenes, Salmonella typhimurium, and Mycobacterium bovis. Am J Vet Res 49(7):1188–1192
Ziprin RL, Corrier DE, Ziegler HK (1987a) T-2 toxin-enhanced resistance against listeriosis in mice: importance of gastrointestinal lesions. Am J Vet Res 48(6):998–1002
Ziprin RL, Holt PS, Morgensen RF (1987b) T-2 toxin effects on the serum amyloid P-component (SAP) response of Listeria monocytogenes- and Salmonella typhimurium-infected mice. Toxicol Lett 39:177–184
Zuk M, Stoehr AM (2002) Immune defense and host life history. Am Nat 160:9–22
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant No. 31602114 and 31572575), the Yangtze Fund for Youth Teams of Science and Technology Innovation (2016cqt02), the Fundamental Research Funds for the Central Universities (2662016PY115), and the project of long-term development plan UHK.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Ethics statement
The manuscript does not contain clinical trials or patient data.
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Wu, Q., Wang, X., Nepovimova, E. et al. Trichothecenes: immunomodulatory effects, mechanisms, and anti-cancer potential. Arch Toxicol 91, 3737–3785 (2017). https://doi.org/10.1007/s00204-017-2118-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-017-2118-3