Pestka J J, Zhou H-R
Department of Food Science and Human Nutrition, 234 G.M. Trout Building, East Lansing, MI 48824-1224, USA.
Food Chem Toxicol. 2002 Nov;40(11):1623-31. doi: 10.1016/s0278-6915(02)00153-9.
Dietary exposure of mice to vomitoxin (VT), a trichothecene mycotoxin, causes anorexia and impaired growth as well as inducing elevated serum IgA and kidney mesangial IgA deposition in a manner analogous to human IgA nephropathy. Based on the observations that TNF-alpha is induced by in vitro and in vivo VT exposure, it was hypothesized that this cytokine plays a role in the nutritional and immunological effects of this toxin. To test this hypothesis, the effects of dietary VT on feed intake, weight gain, serum IgA levels and kidney mesangial IgA deposition in mice homozygous for targeted disruption of the two known TNF-alpha cell surface receptors, TNFR1(p55) or TNFR2(p75), were compared to effects in corresponding C57BL/6J wild-type (WT) mice with normal receptor function. The capacity of VT to cause feed refusal or impair weight gain over a 12-week feeding period was not impaired in TNFR1 knockout (KO) or TNFR2-KO as compared to WT mice. Both WT and TNFR-KO mice fed VT exhibited reduced (P<0.05) feed conversion efficiency, but surprisingly, feed conversion efficiency was significantly higher (P<0.05) in TNFR1-KO and TNFR2-KO fed either control or VT diets than in corresponding WT mice. By week 12, serum IgA concentrations in all three mouse groups fed VT were significantly higher than those for corresponding mice fed control diets (P<0.05). Serum IgA levels in the VT-fed TNFR1-KO group were significantly less (P<0.05) than those for the VT-fed WT mice at 4, 8 and 12 weeks, whereas no differences in this parameter were found between the TNFR2-KO and WT groups. Serum IgA immune complex concentrations were measured at wk 12 and found to follow an identical pattern to IgA. Kidneys taken from VT-fed TNFR2-KO and WT mice after 12 weeks had significantly increased mesangial IgA deposition as compared to controls. While slight increases in mesangial IgA were also observed in VT-fed TNFR1-KO mice, these levels were significantly less (P<0.05) than that found in VT-fed TNFR2-KO and WT mice. Taken together, the data suggest that while VT-mediated anorexic and growth effects were largely independent of TNF-alpha, VT-induced dysregulation of IgA production was dependent, in part, on the interaction of TNF-alpha with TNFR1.
小鼠饮食中接触呕吐毒素（VT，一种单端孢霉烯族霉菌毒素）会导致厌食和生长受损，还会以类似于人类IgA肾病的方式诱导血清IgA升高和肾脏系膜IgA沉积。基于体外和体内VT暴露可诱导肿瘤坏死因子-α（TNF-α）这一观察结果，推测该细胞因子在这种毒素的营养和免疫效应中起作用。为验证这一假设，将饮食中VT对两种已知TNF-α细胞表面受体TNFR1（p55）或TNFR2（p75）靶向敲除纯合子小鼠的采食量、体重增加、血清IgA水平和肾脏系膜IgA沉积的影响，与受体功能正常的相应C57BL/6J野生型（WT）小鼠的影响进行了比较。与WT小鼠相比，在12周的喂养期内，TNFR1基因敲除（KO）或TNFR2-KO小鼠中VT导致拒食或体重增加受损的能力并未受损。喂食VT的WT和TNFR-KO小鼠的饲料转化效率均降低（P<0.05），但令人惊讶的是，喂食对照或VT饮食的TNFR1-KO和TNFR2-KO小鼠的饲料转化效率显著高于（P<0.05）相应的WT小鼠。到第12周时，所有三组喂食VT的小鼠血清IgA浓度均显著高于喂食对照饮食的相应小鼠（P<0.05）。在第4、8和12周时，喂食VT的TNFR1-KO组血清IgA水平显著低于（P<0.05）喂食VT的WT小鼠，而TNFR2-KO组和WT组之间在该参数上未发现差异。在第12周时测量血清IgA免疫复合物浓度，发现其与IgA呈现相同模式。12周后，与对照组相比，喂食VT的TNFR2-KO和WT小鼠的肾脏系膜IgA沉积显著增加。虽然在喂食VT的TNFR1-KO小鼠中也观察到系膜IgA略有增加，但这些水平显著低于（P<0.05）喂食VT的TNFR2-KO和WT小鼠。综上所述，数据表明，虽然VT介导的厌食和生长效应在很大程度上独立于TNF-α，但VT诱导的IgA产生失调部分依赖于TNF-α与TNFR1的相互作用。
