Systems approaches to modeling chronic mucosal inflammation

Mridul Kalita, Bing Tian, Boning Gao, Sanjeev Choudhary, Thomas G. Wood, Joseph R. Carmical, Istvan Boldogh, Sankar Mitra, John D. Minna, Allan R. Brasier

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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-B pathways. Simulation experiments demonstrate that rapid, coordinated cap-independent translation of TRAF-1 and NF-B2 is required to reduce the noncanonical pathway coupling interval. Experiments using amantadine confirmed the prediction that TRAF-1 and NF-B2/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.

Original languageEnglish (US)
Article number505864
JournalBioMed Research International
Volume2013
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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