Abstract
UGRP1 is a downstream target gene for homeodomain transcription factor T/EBP/NKX2.1, which is predominantly expressed in lung epithelial cells, and may play an anti-inflammatory role in lung inflammation. To understand the role of UGRP1 in inflammation, its expression was investigated in relation to cytokine signaling. In vivo experiments using mouse embryonic lung organ culture and intranasal administration of interleukin (IL) 10 revealed that constitutive expression of Ugrp1 mRNA is enhanced by IL-10. Increase of protein levels was also demonstrated by immunohistochemistry using embryonic lungs. This IL-10 induction of Ugrp1 gene expression occurs at the transcriptional level when examined using mouse embryonic lung primary cultures. In human lung NCI-H441 cells that in contrast to mouse lung cells, do not exhibit constitutive expression of the gene, expression of the UGRP1 gene was induced in a rapid and stable fashion. Two T/EBP, but not STAT3, binding sites located in the human UGRP1 gene promoter are responsible for IL-10 induction of the UGRP1 gene as judged by transfection, gel shift, and chromatin immunoprecipitation analyses. The IL-10 receptor chains, IL-10R1 and IL-10R2, are expressed in H441 cells, however, STAT3 was only weakly activated upon IL-10 treatment. In contrast, STAT3 was strongly activated when the cells were treated with other cytokines such as IL-22 and interferon-beta but UGRP1 expression was not increased. Together these results demonstrate that IL-10 induces UGRP1 gene expression in lung epithelial cells through a T/EBP/NKX2.1-dependent pathway. The results further suggest that UGRP1 might be a target for IL-10 anti-inflammatory activities in the lung.
Highlights
Uteroglobin-related protein 1 (UGRP1) is a downstream target gene for homeodomain transcription factor T/EBP/NKX2.1, which is predominantly expressed in lung epithelial cells, and may play an anti-inflammatory role in lung inflammation
The organ-cultured embryonic lungs exhibited an increase in Ugrp1 mRNA levels in a statistically significant time-dependent manner at 48 h after the initiation of IL-10 treatment (Fig. 1A), and intranasal IL-10 administration demonstrated a dose-dependent increase of Ugrp1 mRNA levels after 24 h, with 600 ng being statistically significant (Fig. 1B)
When embryonic lungs were subjected to immunohistochemistry, the increase of UGRP1 protein expression after IL-10 treatment was clearly observed as compared with control, whereas no changes were seen for T/EBP expression with or without IL-10 (Fig. 1C)
Summary
Vol 279, No 52, Issue of December 24, pp. 54358 –54368, 2004 Printed in U.S.A. Interleukin-10 Induces Uteroglobin-related Protein (UGRP) 1 Gene Expression in Lung Epithelial Cells through Homeodomain Transcription Factor T/EBP/NKX2.1*□S. UGRP1 is a downstream target gene for homeodomain transcription factor T/EBP/NKX2.1, which is predominantly expressed in lung epithelial cells, and may play an anti-inflammatory role in lung inflammation. STAT3 was strongly activated when the cells were treated with other cytokines such as IL-22 and interferon- but UGRP1 expression was not increased Together these results demonstrate that IL-10 induces UGRP1 gene expression in lung epithelial cells through a T/EBP/NKX2.1-dependent pathway. The IL-10 responsiveness of UGRP1 gene expression is mediated through the binding of T/EBP, but not STAT3, to its specific binding sites in the promoter region of the UGRP1 gene This is the first demonstration that the homeodomain transcription factor, T/EBP, plays an essential role in mediating the induction of an IL-10 responsive gene in lung epithelial cells, and UGRP1 might be a target for IL-10 anti-inflammatory activities in the lung
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