Crowthers K C, Kline V, Giardina C, Lynes M A
Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut 06269, USA.
Toxicol Appl Pharmacol. 2000 Aug 1;166(3):161-72. doi: 10.1006/taap.2000.8961.
Stress response proteins can play integral roles as modulators of cellular function and can be involved in mechanisms that are important to immune function. Metallothionein (MT), a cysteine-rich stress response protein, has been shown to play numerous roles in the cell: it serves as a reservoir of essential heavy metals, it scavenges free radicals, and it can sequester heavy metals. These various functions suggest that MT may also participate in modulating immune responses. In previous work, we have shown that exogenous metallothionein can suppress the developing humoral immune response when coinjected with antigen. The present study was designed to evaluate the effects of endogenous MT on the development of humoral immunity. We compared the humoral immune function of animals with a targeted disruption of Mt-1 and -2 genes (MTKO) and their wild-type counterparts. MTKO mice displayed a significantly higher humoral response to challenge with ovalbumin (OVA) compared to wild-type controls. The secondary anti-OVA response in MTKO mice is as much as 58% higher than the response in control mice injected at the same time. Overall circulatory immunoglobulin levels are also substantially higher in MTKO mice (0.039 mg/ml IgM and 0.42 mg/ml IgG) than wild-type controls. MTKO mice displayed increased B cell differentiation following OVA challenge and an enhanced lymphoproliferative response to mitogenic stimulation. These changes in immune functional capacity occur in the context of changes in the makeup of the lymphoid compartments of the blood and spleen. There are substantially fewer T and B cells in the circulation of MTKO mice, but more T cells in the spleen of these mice than in control animals. Finally, we have found that splenocytes from MTKO animals displayed significantly elevated levels of NF-kappaB activity compared to wild-type controls. In conclusion, we have provided evidence that endogenous metallothionein can modulate the immune response in vivo and that intracellular MT may modulate immune function by regulation of transcription factor activity.
应激反应蛋白可作为细胞功能的调节因子发挥不可或缺的作用，并可参与对免疫功能至关重要的机制。金属硫蛋白（MT）是一种富含半胱氨酸的应激反应蛋白，已被证明在细胞中发挥多种作用：它作为必需重金属的储存库，清除自由基，并能螯合重金属。这些多样的功能表明MT可能也参与调节免疫反应。在之前的研究中，我们已经表明，外源性金属硫蛋白与抗原共同注射时可抑制正在发育的体液免疫反应。本研究旨在评估内源性MT对体液免疫发育的影响。我们比较了Mt-1和-2基因靶向敲除（MTKO）动物及其野生型对照的体液免疫功能。与野生型对照相比，MTKO小鼠对卵清蛋白（OVA）攻击表现出显著更高的体液反应。MTKO小鼠的二次抗OVA反应比同时注射的对照小鼠的反应高出多达58%。MTKO小鼠的总体循环免疫球蛋白水平（0.039 mg/ml IgM和0.42 mg/ml IgG）也显著高于野生型对照。OVA攻击后，MTKO小鼠的B细胞分化增加，对有丝分裂原刺激的淋巴细胞增殖反应增强。免疫功能能力的这些变化发生在血液和脾脏淋巴区室组成变化的背景下。MTKO小鼠循环中的T和B细胞明显较少，但这些小鼠脾脏中的T细胞比对照动物多。最后，我们发现与野生型对照相比，MTKO动物的脾细胞显示出显著升高的NF-κB活性水平。总之，我们提供了证据表明内源性金属硫蛋白可在体内调节免疫反应，并且细胞内MT可能通过调节转录因子活性来调节免疫功能。
