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The Signaling Pathway Involved in Neutrophil Elastase–Stimulated MUC1 Transcription

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

Correspondence and requests for reprints should be addressed to K. Chul Kim, Ph.D., Lovelace Respiratory Research Institute, 2425 Ridgecrest Dr. SE, Albuquerque, NM 87108-5127. 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 protein kinase C (PKC) dual oxidase 1 (Duox1) reactive oxygen species (ROS) TNF-–converting enzyme (TACE) TNF- 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-, 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- suggests a crucial role for MUC1 in the control of excessive inflammation during airway bacterial infection.

Key Words: neutrophil elastase • MUC1 • signaling • airway

CLINICAL RELEVANCE This article describes, for the first time, a complete signaling pathway involved in neutrophil elastase–induced MUC1 transcription, which is very important for basic science and highly useful for clinical medicine.