Lim Jae Hyang, Kim Hyun-Jung, Komatsu Kensei, Ha Unhwan, Huang Yuxian, Jono Hirofumi, Kweon Soo-Mi, Lee Jiyun, Xu Xiangbin, Zhang Gen-Sheng, Shen Huahao, Kai Hirofumi, Zhang Wenhong, Xu Haidong, Li Jian-Dong
Am J Transl Res. 2009 May 8;1(3):300-11.
Human epithelial mucin, the major glycoprotein component of mucus, plays a critical role in host innate defense response against invading microbes by facilitating the mucociliary clearance. Excess mucin production, however, overwhelms the mucociliary clearance, resulting in not only defective mucosal defense but also conductive hearing loss in the middle ear and mucus obstruction in the airway. Indeed, mucus overproduction is a hall-mark of otitis media (OM) and chronic obstructive pulmonary diseases (COPD). Thus, tight regulation of mucin production plays an important role in maintaining an appropriate balance between beneficial and detrimental outcomes. We previously reported that Streptococcus pneumoniae (S. pneumoniae) up-regulates MUC5AC mucin expression via a positive MAPK ERK1/2 and a negative JNK1/2 signaling pathway. However, the signaling components including the up-stream activators and the down-stream transcription factors involved in these two path-ways remain largely unknown. In the present study, we showed that positive regulation of MUC5AC mucin expression by ERK1/2 is dependent on Ras-Raf-1 signaling pathway, whereas the negative regulation of MUC5AC expression by JNK1/2 is dependent on MEKK3. Moreover, transcriptional factor AP-1 acts as a key regulator for both of the positive and negative regulation of MUC5AC mucin expression as evidenced by mutagenesis analysis of two AP-1 sites in the promoter region of human MUC5AC mucin gene. Ras-Raf1-ERK1/2-dependent AP-1 activation positively regulates MUC5AC mucin induction by S. pneumoniae, whereas MEKK3-JNK1/2-dependent AP-1 activation negatively regulates it. Therefore, our data unveiled a novel signaling mechanism underlying the tight regulation of MUC5AC mucin induction by S. pneumoniae and may lead to the development of new therapeutic strategy for reducing mucus overproduction in both OM and COPD.
人上皮黏液素是黏液的主要糖蛋白成分，通过促进黏液纤毛清除，在宿主针对入侵微生物的固有防御反应中发挥关键作用。然而，黏液素产生过多会使黏液纤毛清除不堪重负，不仅导致黏膜防御功能缺陷，还会引起中耳传导性听力损失和气道黏液阻塞。事实上，黏液过度产生是中耳炎（OM）和慢性阻塞性肺疾病（COPD）的一个标志。因此，严格调控黏液素的产生对于维持有益和有害结果之间的适当平衡起着重要作用。我们之前报道过，肺炎链球菌（S. pneumoniae）通过正向的MAPK ERK1/2和负向的JNK1/2信号通路上调MUC5AC黏液素的表达。然而，参与这两条通路的信号成分，包括上游激活剂和下游转录因子，在很大程度上仍然未知。在本研究中，我们表明ERK1/2对MUC5AC黏液素表达的正向调控依赖于Ras-Raf-1信号通路，而JNK1/2对MUC5AC表达的负向调控依赖于MEKK3。此外，转录因子AP-1作为MUC5AC黏液素表达正向和负向调控的关键调节因子，这一点通过对人MUC5AC黏液素基因启动子区域两个AP-1位点的诱变分析得到了证实。Ras-Raf1-ERK1/2依赖的AP-1激活正向调节肺炎链球菌诱导的MUC5AC黏液素，而MEKK3-JNK1/2依赖的AP-1激活则对其起负向调节作用。因此，我们的数据揭示了肺炎链球菌对MUC5AC黏液素诱导进行严格调控的一种新的信号机制，可能会为减少OM和COPD中黏液过度产生的新治疗策略开发提供线索。
