The signaling pathway involved in neutrophil elastase stimulated MUC1 transcription.
We previously reported that neutrophil elastase (NE) stimulated MUC1 gene expression in A549 lung epithelial cells through binding of Sp1 to the MUC1 promoter element. The current study was undertaken to elucidate the complete signaling pathway leading to Sp1 activation. Using a combination of pharmacologic inhibitors, dominant-negative mutant, RNA interference, and soluble receptor blocking techniques, we identified a protein kinase Cdelta (PKCdelta) --> dual oxidase 1 (Duox1) --> reactive oxygen species (ROS) --> TNF-alpha-converting enzyme (TACE) --> TNF-alpha --> TNF receptor (TNFR)1 --> extracellular signal-regulated kinase (ERK)1/2 --> Sp1 pathway as responsible for NE-activated MUC1 transcription. This cascade was identical up to the point of TACE with the signaling pathway previously reported for NE-stimulated MUC5AC production. However, unlike the MUC5AC pathway, TNF-alpha, TNFR1, ERK1/2, and Sp1 were unique components of the MUC1 pathway. Given the anti-inflammatory role of MUC1 during airway bacterial infection, up-regulation of MUC1 by inflammatory mediators such as NE and TNF-alpha suggests a crucial role for MUC1 in the control of excessive inflammation during airway bacterial infection.
Kuwahara
Ippei
I
Immunology Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108-5127, USA.
Lillehoj
Erik P
EP
Koga
Takeshi
T
Isohama
Yoichiro
Y
Miyata
Takeshi
T
Kim
K Chul
KC
D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000074623:Dual Oxidases; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005420:Flavoproteins / Q000037:antagonists & inhibitors; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism*; D008954:Models, Biological; D018396:Mucin-1 / Q000235:genetics*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000378:metabolism; D010769:Phosphothreonine / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D004791:Enzyme Inhibitors; D005420:Flavoproteins; C060192:MUC1 protein, human; D018396:Mucin-1; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D047888:Receptors, Tumor Necrosis Factor, Type I; D016329:Sp1 Transcription Factor; D010769:Phosphothreonine; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431513:DUOX1 protein, human; D066246:ErbB Receptors; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; D019272:Leukocyte Elastase; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human