Role of cyclooxygenase-2 in deoxynivalenol-induced immunotoxicity

Deoxynivalenol (DON, vomitoxin or VT), one of the trichothecene mycotoxins, has been recognized to cause immune stimulation or immune suppression in the experimental animals dependently on dose regimes. The purpose of this thesis was to determine whether DON affects cyclooxygenase-2 (COX-2) expression and its possible contribution to DON-induced immune dysfunctions. COX-2 was strongly induced in mouse spleens and Peyer's patches by the acute exposure to DON. Using the macrophage as a model for COX-2 production, the gene induction mechanism was investigated. Elevated COX-2 production was found to be due to enhanced transcriptional activation and mRNA stability by DON. DON-activated extracellular signal regulated protein kinases 1 and 2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) played an evident role in enhancing transcriptional activity of COX-2 gene. Moreover, p38 MAPK was strongly involved in the DON-mediated COX-2 mRNA stabilization as well as promoter activation. Type B trichothecenes other than DON, namely, 15-acetyl DON, 3-acetyl DON and fusarenon-X were also potent inducers of COX-2 expression whereas Type A and Type D trichothecenes had less effect on COX-2 expression. Type B trichothecene-induced COX-2 was also regulated via transcriptional and post-transcriptional control of the gene.; Interleukin-6 (IL-6) is known to play a pivotal role in DON-mediated IgA nephropathy (IgAN) and the toxin-induced COX-2 was assessed for its effect on IL-6 production. Blocking with COX-2 inhibitors or genetic ablation using COX-2 knockout mice retarded IL-6 induction by DON. Therefore, DON-mediated IL-6 production was, in part, due to COX-2 induction and its metabolites.; From a therapeutic perspective, dietary fish oil (FO) suppresses DON-induced IgAN in the animal model. To determine the pro-inflammatory gene responses and the signaling molecules related to the disease amelioration by FO, mice were fed with corn oil or fish oil for 8 weeks and then were acutely exposed to DON. Fish oil-fed mice demonstrated significantly reduced IL-6, ERK1/2 and JNK1/2 responses to DON as compared to corn oil-fed mice. However, there was little significant effect of FO on DON-induced COX-2 activity. Mainly present in fish oil, (n-3) polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (20:5(n-3), EPA) or docosahexaenoic acid (22:6(n-3), DHA) strongly decreased DON-mediated IL-6 superinduction in presence of lipopolysaccharide in vitro using RAW 264.7 cells. Moreover, DON-activated ERK1/2 and JNKI/2 were suppressed by pretreatment of the cells with (n-3) PUFA. It is thus assumed that fish oil might retard DON-induced IL-6 production by regulating MAPK signaling pathway.