Tumor necrosis factor-alpha triggers mucus production in airway epithelium through an IkappaB kinase beta-dependent mechanism.
Excessive mucus production by airway epithelium is a major characteristic of a number of respiratory diseases, including asthma, chronic bronchitis, and cystic fibrosis. However, the signal transduction pathways leading to mucus production are poorly understood. Here we examined the potential role of IkappaB kinase beta (IKKbeta) in mucus synthesis in vitro and in vivo. Tumor necrosis factor-alpha (TNF-alpha) or transforming growth factor-alpha stimulation of human epithelial cells resulted in mucus secretion as measured by MUC5AC mRNA and protein. TNF-alpha stimulation induced IKKbeta-dependent p65 nuclear translocation, mucus synthesis, and production of cytokines from epithelial cells. TNF-alpha, but not transforming growth factor-alpha, induced mucus production dependent on IKKbeta-mediated NF-kappaB activation. In vivo, TNF-alpha induced NF-kappaB as determined by whole mouse body bioluminescence. This activation was localized to the epithelium as revealed by LacZ staining in NF-kappaB-LacZ transgenic mice. TNF-alpha-induced mucus production in vivo could also be inhibited by administration into the epithelium of an IKKbeta dominant negative adenovirus. Taken together, our results demonstrated the important role of IKKbeta in TNF-alpha-mediated mucus production in airway epithelium in vitro and in vivo.
Lora
José M
JM
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Zhang
Dong Mei
DM
Liao
Sha Mei
SM
Burwell
Timothy
T
King
Anne Marie
AM
Barker
Philip A
PA
Singh
Latika
L
Keaveney
Marie
M
Morgenstern
Jay
J
Gutiérrez-Ramos
José Carlos
JC
Coyle
Anthony J
AJ
Fraser
Christopher C
CC
D021581:Active Transport, Cell Nucleus; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D003470:Culture Media / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007150:Immunohistochemistry; D007763:Lac Operon; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D055271:Mucin 5AC; D009077:Mucins / Q000378:metabolism; D009093:Mucus / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D050863:Synaptotagmin I / Q000378:metabolism; D013696:Temperature; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation; D001616:beta-Galactosidase / Q000378:metabolism
D003470:Culture Media; D016207:Cytokines; C524678:MUC5AC protein, human; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D009077:Mucins; D012333:RNA, Messenger; D050863:Synaptotagmin I; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; D001616:beta-Galactosidase