Differential regulation of Streptococcus pneumoniae-induced human MUC5AC mucin expression through distinct MAPK pathways.
Differential regulation of Streptococcus pneumoniae-induced human MUC5AC mucin expression through distinct MAPK pathways.
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发表时间：
2009-05
影响因子：
2.2
通讯作者：
J. Lim;Hyun‐Jung Kim;Kensei Komatsu;U. Ha;Yu-xian Huang;H. Jono;S. Kweon;Jiyun Lee;Xiangbin Xu;Gen-sheng Zhang;Huahao Shen;H. Kai;Wenhong Zhang;Haidong Xu;Jian-Dong Li
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作者：
J. Lim;Hyun‐Jung Kim;Kensei Komatsu;U. Ha;Yu-xian Huang;H. Jono;S. Kweon;Jiyun Lee;Xiangbin Xu;Gen-sheng Zhang;Huahao Shen;H. Kai;Wenhong Zhang;Haidong Xu;Jian-Dong Li
人上皮黏液蛋白是黏液的主要糖蛋白成分，通过促进黏液纤毛清除，在宿主对入侵微生物的先天防御反应中起关键作用。然而，过量的黏液蛋白的产生使黏液纤毛的清除受阻，不仅导致粘膜防御缺陷，而且导致中耳传导性听力损失和气道粘液阻塞。事实上，粘液分泌过多是中耳炎（OM）和慢性阻塞性肺疾病（COPD）的标志。因此，严格调节粘蛋白的产生在维持有益和有害结果之间的适当平衡方面起着重要作用。我们之前报道过肺炎链球菌（S. pneumoniae）通过MAPK ERK1/2阳性和JNK1/2阴性信号通路上调MUC5AC粘蛋白表达。然而，包括上游激活因子和下游转录因子在内的信号传导成分在这两种途径中所涉及的信号仍然是未知的。在本研究中，我们发现ERK1/2对MUC5AC粘蛋白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信号通路。此外，转录因子AP-1在MUC5AC粘蛋白基因启动子区域的两个AP-1位点的诱变分析证实，AP-1在MUC5AC粘蛋白表达的正调控和负调控中都起着关键的调节作用。ras - raf1 - erk1 /2依赖性AP-1激活正调控肺炎链球菌诱导MUC5AC粘蛋白，而mekk3 - jnk1 /2依赖性AP-1激活负调控MUC5AC粘蛋白。因此，我们的数据揭示了肺炎链球菌对MUC5AC粘蛋白诱导的严格调控的一种新的信号机制，并可能导致新的治疗策略的发展，以减少OM和COPD的粘液过量产生。
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.