Gene expression profiles of CEBPß-overexpressed alveolar macrophages after A20-Ad treatment

Although recent progressions have provided significant mechanistic insights into the pathogenesis of pulmonary fibrosis (PF), few of anti-PF therapeutics show certain promise for this devastating disease. Chronic or repeated lung injury results in chronic inflammation, which functions as a major driven force to promote PF development. Here we report that chronic lung injury inactivates ubiquitin-modifying enzyme A20 to cause a progressive accumulation of transcription factor C/EBPb in macrophages, which produce a number of pro-fibrotic factors to promote PF development. Elevated GSK-3b expression, in response to chronic lung injury, interacts with and phosphorylates A20 to suppress C/EBPb degradation in macrophages. Enforced expression of A20 or pharmacological acceleration of C/EBPb degradation by a peptide restores the A20 activity and provides potent therapeutic efficacy against experimental PF. Our studies reveal a regulatory mechanism of the GSK-3b-A20-C/EBPb axis in alveolar macrophages, by targeting which can treat PF and fibroproliferative lung diseases. Overall design: mRNA profiles of CEBPß-overexpressed alveolar macrophages after A20-Ad treatment were generated by deep sequencing, in triplicate, using Illumina Hiseq.