Differential regulation of Streptococcus pneumoniae-induced human MUC5AC mucin expression through distinct MAPK pathways

Jae Hyang Lim, Hyun Jung Kim, Kensei Komatsu, Unhwan Ha, Yuxian Huang, Hirofumi Jono, Soo Mi Kweon, Jiyun Lee, Xiangbin Xu, Gen Sheng Zhang, Huahao Shen, Hirofumi Kai, Wenhong Zhang, Haidong Xu, Jian Dong Li

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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 hallmark 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 pathways 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.

Original languageEnglish
Pages (from-to)300-311
Number of pages12
JournalAmerican Journal of Translational Research
Volume1
Issue number3
StatePublished - 2009

Keywords

  • AP-1
  • COPD
  • ERK
  • JNK
  • MUC5AC mucin
  • Otitis media
  • Streptococcus pneumonia

Fingerprint

Dive into the research topics of 'Differential regulation of Streptococcus pneumoniae-induced human MUC5AC mucin expression through distinct MAPK pathways'. Together they form a unique fingerprint.

Cite this