Foster L C, Arkonac B M, Sibinga N E, Shi C, Perrella M A, Haber E
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
J Biol Chem. 1998 Aug 7;273(32):20341-6. doi: 10.1074/jbc.273.32.20341.
The CD44 gene codes for a family of alternatively spliced, multifunctional adhesion molecules that participate in extracellular matrix binding, lymphocyte activation, cell migration, and tumor metastasis. In a mouse model of transplant-associated arteriosclerosis, CD44 protein was induced in the neointima of allografted vessels and colocalized with a subset of proliferating vascular smooth muscle cells (SMC). To elucidate the molecular mechanisms regulating CD44 expression in this model, we investigated the regulation of CD44 gene expression by interleukin (IL)-1beta. Treatment of rat aortic SMC with IL-1beta resulted in a 5.3-fold increase in cell surface CD44 expression. Northern analysis showed that IL-1beta promoted a dose- and time-dependent induction of CD44 mRNA which reached 6.6-fold after 48 h, and nuclear run-on analysis showed that IL-1beta increased the rate of CD44 gene transcription within 8 h of stimulation. In transient reporter gene transfection experiments in rat aortic SMC, a 1.4-kilobase fragment of the mouse CD44 5'-flanking sequence mediated this response to IL-1beta. Regulation of CD44 gene expression by the proinflammatory cytokine IL-1beta may contribute to SMC phenotypic modulation in the pathogenesis of arteriosclerosis.
CD44基因编码一类可变剪接的多功能黏附分子家族，这些分子参与细胞外基质结合、淋巴细胞活化、细胞迁移和肿瘤转移。在移植相关性动脉硬化的小鼠模型中，CD44蛋白在同种异体移植血管的新生内膜中被诱导表达，并与一部分增殖的血管平滑肌细胞（SMC）共定位。为了阐明该模型中调控CD44表达的分子机制，我们研究了白细胞介素（IL）-1β对CD44基因表达的调控作用。用IL-1β处理大鼠主动脉SMC后，细胞表面CD44表达增加了5.3倍。Northern分析表明，IL-1β促进了CD44 mRNA的剂量和时间依赖性诱导，48小时后达到6.6倍，核转录分析表明，IL-1β在刺激8小时内增加了CD44基因的转录速率。在大鼠主动脉SMC的瞬时报告基因转染实验中，小鼠CD44 5'侧翼序列的1.4千碱基片段介导了对IL-1β的这种反应。促炎细胞因子IL-1β对CD44基因表达的调控可能在动脉硬化发病机制中有助于SMC表型调节。
