CCAAT/Enhancer-Binding Protein γ Is a Critical Regulator of IL-1β-Induced IL-6 Production in Alveolar Epithelial Cells

Chunguang Yan,Hongwei Gao,Jay Cao,Min Wu,Ximo Wang

doi:10.1371/journal.pone.0035492

Abstract

CCAAT/enhancer binding protein γ (C/EBPγ) is a member of the C/EBP family of transcription factors, which lacks known activation domains. C/EBPγ was originally described as an inhibitor of C/EBP transactivation potential. However, previous study demonstrates that C/EBPγ augments the C/EBPβ stimulatory activity in lipopolysaccharide induction of IL-6 promoter in a B lymphoblast cell line. These data indicate a complexing functional role for C/EBPγ in regulating gene expression. Furthermore, the expression and function of C/EBPγ during inflammation are still largely unknown. In this study, we demonstrate that C/EBPγ activation was induced by IL-1β treatment in lung epithelial cells. Importantly, we demonstrate for the first time that C/EBPγ plays a critical role in regulating IL-1β-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/EBPγ inhibits IL-6 expression by inhibiting C/EBPβ but not NF-κB stimulatory activity in MLE12 cells. These findings suggest that C/EBPγ 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.

Highlights

As one of the major cell types comprising alveolar epithelial tissue, the alveolar type II epithelial cells play an important role in maintaining alveolar integrity by forming the key alveolar barrier, repairing damaged type I cells, and being the source of alveolar surfactant [1,2,3]
Previous study shows that CCAAT/enhancer binding protein c (C/EBPc) dramatically augments the activity of C/EBPb in LPS induction of the IL-6 and IL-8 promoters in a B lymphoblast cell line [16]
We show that C/EBPc expression is induced by IL-1b in alveolar type II epithelial cells

Summary

Introduction

As one of the major cell types comprising alveolar epithelial tissue, the alveolar type II epithelial cells play an important role in maintaining alveolar integrity by forming the key alveolar barrier, repairing damaged type I cells, and being the source of alveolar surfactant [1,2,3]. Increasing studies suggest a critical role for alveolar type II epithelial cells in regulating local lung inflammatory response. Our previous study and others have suggested that alveolar type II epithelial cells may play special roles in counteracting microbes by releasing cytokines and chemokines that recruit both dendritic cells and alveolar macrophages to the site of infection [4,5,6,7]. The potential role of alveolar type II epithelial cells in lung innate immunity and the molecular mechanisms whereby the expressions of inflammatory mediators are regulated in alveolar type II epithelial cells remain largely unknown. IL-1b is known to modulate the activity of many transcription factors including NF-kB and C/EBPs. the role of C/EBPs in IL-1b-mediated inflammatory responses in alveolar type II epithelial cells remains unknown. The goal of the current study was to investigate the role of C/EBPc in IL-1bstimulated IL-6 production from alveolar type II epithelial cells

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