Interleukin-10 induces uteroglobin-related protein (UGRP) 1 gene expression in lung epithelial cells through homeodomain transcription factor T/EBP/NKX2.1.
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. 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.
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Achara
A
Srisodsai
Reiko
R
Kurotani
Yoshihiko
Y
Chiba
Faruk
F
Sheikh
Howard A
HA
Young
Raymond P
RP
Donnelly
Shioko
S
Kimura
D000230:Adenocarcinoma; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian; D004847:Epithelial Cells / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000494:pharmacology*; D008168:Lung / Q000737:chemistry / Q000378:metabolism*; D008175:Lung Neoplasms; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D009924:Organ Culture Techniques; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D018123:Receptors, Interleukin / Q000235:genetics / Q000502:physiology; D053701:Receptors, Interleukin-10; D050796:STAT3 Transcription Factor; D060765:Secretoglobins; D000074482:Thyroid Nuclear Factor 1; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014598:Uteroglobin
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; C449940:SCGB3A2 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C449818:Scgb3a2 protein, mouse; D060765:Secretoglobins; C494087:Stat3 protein, mouse; D000074482:Thyroid Nuclear Factor 1; D015534:Trans-Activators; D014157:Transcription Factors; D016753:Interleukin-10; D004247:DNA; D014598:Uteroglobin