CCAAT/Enhancer-Binding Protein \(\gamma\) Is a Critical Regulator of IL-1\(\beta\)-Induced IL-6 Production in Alveolar Epithelial Cells

CCAAT/enhancer binding protein c (C/EBPc) is a member of the C/EBP family of transcription factors, which lacks known activation domains. C/EBPc was originally described as an inhibitor of C/EBP transactivation potential. However, previous study demonstrates that C/EBPc augments the C/EBPb stimulatory activity in lipopolysaccharide induction of IL-6 promoter in a B lymphoblast cell line. These data indicate a complexing functional role for C/EBPc in regulating gene expression. Furthermore, the expression and function of C/EBPc during inflammation are still largely unknown. In this study, we demonstrate that C/EBPc activation was induced by IL-1b treatment in lung epithelial cells. Importantly, we demonstrate for the first time that C/EBPc plays a critical role in regulating IL-1b-induced IL-6 expression in both mouse primary alveolar type II epithelial cells and a lung epithelial cell line, MLE12. We further provide the evidence that C/EBPc inhibits IL-6 expression by inhibiting C/EBPb but not NF-kB stimulatory activity in MLE12 cells. These findings suggest that C/EBPc is a key transcription factor that regulates the IL-6 expression in alveolar epithelial cells, and may play an important regulatory role in lung inflammatory responses. Citation: Yan C, Wang X, Cao J, Wu M, Gao H (2012) CCAAT/Enhancer-Binding Protein c Is a Critical Regulator of IL-1b-Induced IL-6 Production in Alveolar Epithelial Cells. PLoS ONE 7(4): e35492. doi:10.1371/journal.pone.0035492 Editor: Hong Wei Chu, National Jewish Health, United States of America Received January 17, 2012; Accepted March 19, 2012; Published April 27, 2012 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: This research was supported by NIH grants 5R01HL092905-04 and 3R01HL092905-02S1 (HG) and the USDA Agricultural Research Service (ARS) program ‘‘Mineral Intakes for Optimal Bone Development and Health,’’ Current Research Information System (CRIS) no. 5450-51000-046-00D (JC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] (HG); [email protected] (MW)