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Published ahead of print on June 28, 2007, doi:10.1165/rcmb.2007-0072OC

Am. J. Respir. Cell Mol. Biol., Volume 37, Number 6, December 2007, 691-698

A more recent version of this article appeared on December 1, 2007
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Submitted on March 3, 2007
Revised on June 28, 2007

The Signaling Pathway Involved in Neutrophil Elastase-Stimulated MUC1 Transcription

Ippei Kuwahara1, Erik P Lillehoj2, Takeshi Koga3, Yoichiro Isohama4, Takeshi Miyata5, and K. Chul Kim1*

1 Immunology Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA, 2 Department of Pediatrics, University of Maryland, School of Medicine, Baltimore, MD, USA, 3 Immunology Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA; Department of Chemico-Pharmacology, Kumamoto University, Graduate School of Medicine and Pharmacy, Kumamoto, Japan, 4 Department of Chemico-Pharmacology, Kumamoto University, Graduate School of Medicine and Pharmacy, Kumamoto, Japan, 5 Laboratory of Presymptomatic Medical Pharmacology, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan

* To whom correspondence should be addressed. E-mail: kckim{at}LRRI.org.

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 PKC{delta} {Rightarrow} Duox1 {Rightarrow} ROS {Rightarrow} TACE {Rightarrow} TNF-{alpha} {Rightarrow} TNFR1 {Rightarrow} ERK1/2 {Rightarrow} 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.




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