Abstract
IL-33 is a cytokine central to type 2 immune pathology in chronic airway disease. This cytokine is abundantly expressed in the respiratory epithelium and increased in disease, but how expression is regulated is undefined. Here we show that increased IL33 expression occurs from multiple noncanonical promoters in human chronic obstructive pulmonary disease (COPD), and it facilitates production of alternatively spliced isoforms in airway cells. We found that phorbol 12-myristate 13-acetate (PMA) can activate IL33 promoters through protein kinase C in primary airway cells and lines. Transcription factor (TF) binding arrays combined with RNA interference identified activator protein (AP) TFs as regulators of baseline and induced IL33 promoter activity. ATAC-Seq and ChIP-PCR identified chromatin accessibility and differential TF binding as additional control points for transcription from noncanonical promoters. In support of a role for these TFs in COPD pathogenesis, we found that AP-2 (TFAP2A, TFAP2C) and AP-1 (FOS and JUN) family members are upregulated in human COPD specimens. This study implicates integrative and pioneer TFs in regulating IL33 promoters and alternative splicing in human airway basal cells. Our work reveals a potentially novel approach for targeting IL-33 in development of therapeutics for COPD.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.