Transcriptional Regulation of Matrix Metalloproteinase-3

描述：在牙周炎中，炎性细胞因子IL-1水平较高且与疾病严重程度相关，而抗炎IL-4水平较低或检测不到，IL-4水平下降与疾病严重程度相关。IL-1通过增加基质金属蛋白酶的表达而导致附着丧失和牙槽骨破坏。基质金属蛋白酶-3具有广泛的底物特异性，可以激活其他基质金属蛋白酶原。在疾病部位发现它的水平增加，并且水平与严重程度和进展相关。先前的研究证实SIRE位点(基质分解蛋白IL-1反应元件)是参与抑制IL-1诱导的基质金属蛋白酶-3的抑制元件。其他人也发现该位点是一种常见的5T/6T多态，其中6T位点是一种更有效的抑制元件。该位点的基因型与组织中的基质金属蛋白酶-3水平以及许多疾病的易感性或严重程度有关。在心血管疾病(一种与牙周炎相关的疾病)中，高表达的5T等位基因的纯合与心肌梗死和动脉瘤有关，而低表达的6T等位基因与动脉粥样硬化有关。因此，很明显，必须严格控制该基因的调节，以维持正确的组织动态平衡，并且了解这些控制机制对于各种病理来说都是重要的。我们最近发现与SIRE位点结合的蛋白质包括NF-kappaB p50、p65和ZBP-89。我们最近还发现，从牙周炎患者分离的人牙龈成纤维细胞中，IL-1对基质金属蛋白酶-3的诱导可被IL-4抑制。本应用的具体目的是：1)研究转录因子与MMP3启动子中SIRE位点多态相互作用的作用；2)确定IL-4抑制MMP3表达的机制。通过这样做，我们希望获得涉及基质金属蛋白酶-3调控的复杂基因调控机制的信息，同时也继续为PCOM的研究环境和对其学生进行一般研究，特别是分子生物学方面的培训做出贡献。

DESCRIPTION: In periodontitis, levels of inflammatory cytokine IL-1 are high and correlate with disease severity, while levels of anti-inflammatory IL-4 are low or undetectable and decreasing levels of IL-4 correlate with increasing severity. IL-1 contributes to loss of attachment and alveolar bone destruction by increasing expression of matrix metalloproteinases. MMP-3 has broad substrate specificity and can activate other pro-MMP. It is found in increased levels in diseased sites, and levels are correlated with severity and progression. Previous studies identified the SIRE site (stromelysin IL-1 responsive element) as a repressor element involved in suppressing the IL-1 induction of MMP-3. Others also identified this site as a common 5T/6T polymorphism, with the 6T site being a more effective repressor element. Genotype at this site has been linked to tissue levels of MMP-3 and to susceptibility or severity of a number of diseases. In cardiovascular disease (a condition associated with periodontitis), homozygosity for the higher-expressing 5T allele is associated with myocardial infarction and aneurysm, while the lower-expressing 6T allele is associated with atherosclerosis. It is therefore clear that regulation of this gene must be tightly controlled to maintain correct tissue homeostasis, and that understanding these control mechanisms is important for a variety of pathologies. We recently found that proteins binding to the SIRE site include NF-kappaB p50 and p65 and ZBP-89. We also recently showed that IL-1 induction of MMP-3 is suppressed by IL-4 in human gingival fibroblasts isolated from patients with periodontitis. The Specific Aims of this application are to: 1) study the roles of transcription factors interacting with the polymorphic SIRE site in the MMP-3 promoter, and 2) determine the mechanism of suppression of MMP-3 expression by IL-4. In doing so, we hope to gain information about complex gene regulatory mechanisms involved in MMP-3 regulation, but also continue to contribute to the research environment at PCOM and to the training of its students in research in general, and molecular biology in particular.