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BioMed Research International
Volume 2013 (2013), Article ID 505864, 17 pages
http://dx.doi.org/10.1155/2013/505864
Research Article

Systems Approaches to Modeling Chronic Mucosal Inflammation

1Sealy Center for Molecular Medicine, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA
2Department of Internal Medicine, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA
3Hamon Center for Therapeutic Oncology Research, Department of Internal Medicine Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
4Institute for Translational Sciences, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA
5Departments of Biochemistry and Molecular Biology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA
6Microbiology and Immunology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA

Received 12 June 2013; Revised 8 August 2013; Accepted 9 August 2013

Academic Editor: Tao Huang

Copyright © 2013 Mridul Kalita et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The respiratory mucosa is a major coordinator of the inflammatory response in chronic airway diseases, including asthma and chronic obstructive pulmonary disease (COPD). Signals produced by the chronic inflammatory process induce epithelial mesenchymal transition (EMT) that dramatically alters the epithelial cell phenotype. The effects of EMT on epigenetic reprogramming and the activation of transcriptional networks are known, its effects on the innate inflammatory response are underexplored. We used a multiplex gene expression profiling platform to investigate the perturbations of the innate pathways induced by TGFβ in a primary airway epithelial cell model of EMT. EMT had dramatic effects on the induction of the innate pathway and the coupling interval of the canonical and noncanonical NF-κB pathways. Simulation experiments demonstrate that rapid, coordinated cap-independent translation of TRAF-1 and NF-κB2 is required to reduce the noncanonical pathway coupling interval. Experiments using amantadine confirmed the prediction that TRAF-1 and NF-κB2/p100 production is mediated by an IRES-dependent mechanism. These data indicate that the epigenetic changes produced by EMT induce dynamic state changes of the innate signaling pathway. Further applications of systems approaches will provide understanding of this complex phenotype through deterministic modeling and multidimensional (genomic and proteomic) profiling.