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Am J Translational Res 1(3):300-311,2009
Original Article
Differential regulation of Streptococcus pneumoniae-induced human
MUC5AC mucin expression through distinct MAPK pathways
Jae Hyang Lim1, 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
From Department of Microbiology & Immunology, University of Rochester Medical Center, Rochester, NY 14642,
USA; Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200433, China;
Department of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, Korea
399-700; Department of Molecular Medicine, Kumamoto University, Kumamoto 862-0973, Japan; Department of
Respiratory Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang
310009, China
Received March 6, 2009; accepted May 5, 2009; available online May 8, 2009
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 gene. Ras-Raf1-ERK1/2-
dependent AP-1 activation positively regulates MUC5AC mucin induction by S. penumoniae, 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.(AJTR903003).
Key Words: MUC5AC mucin, Streptococcus pneumoniae, ERK, JNK, AP-1, Otitis Media
Full Text PDF
Address all correspondence to:
Jian-Dong Li, MD, PhD,
Department of Microbiology & Immunology
Box 672, University of Rochester Medical Center
601 Elmwood Avenue
Rochester, NY 14642
USA.
Tel. 585-275-7195; Fax. 585-276-233
E-mail: Jian-Dong_Li@urmc.rochester.edu
Original Article
Differential regulation of Streptococcus pneumoniae-induced human
MUC5AC mucin expression through distinct MAPK pathways
Jae Hyang Lim1, 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
From Department of Microbiology & Immunology, University of Rochester Medical Center, Rochester, NY 14642,
USA; Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200433, China;
Department of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, Korea
399-700; Department of Molecular Medicine, Kumamoto University, Kumamoto 862-0973, Japan; Department of
Respiratory Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang
310009, China
Received March 6, 2009; accepted May 5, 2009; available online May 8, 2009
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 gene. Ras-Raf1-ERK1/2-
dependent AP-1 activation positively regulates MUC5AC mucin induction by S. penumoniae, 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.(AJTR903003).
Key Words: MUC5AC mucin, Streptococcus pneumoniae, ERK, JNK, AP-1, Otitis Media
Full Text PDF
Address all correspondence to:
Jian-Dong Li, MD, PhD,
Department of Microbiology & Immunology
Box 672, University of Rochester Medical Center
601 Elmwood Avenue
Rochester, NY 14642
USA.
Tel. 585-275-7195; Fax. 585-276-233
E-mail: Jian-Dong_Li@urmc.rochester.edu
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