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J. Biol. Chem., Vol. 279, Issue 52, 54358-54368, December 24, 2004

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Interleukin-10 Induces Uteroglobin-related Protein (UGRP) 1 Gene Expression in Lung Epithelial Cells through Homeodomain Transcription Factor T/EBP/NKX2.1^*

Achara Srisodsai, Reiko Kurotani, Yoshihiko Chiba¶, Faruk Sheikh||, Howard A. Young**, Raymond P. Donnelly||, and Shioko Kimura

From the Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, the ^||Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, and the ^**Laboratory of Experimental Immunology, National Cancer Institute, Frederick, Maryland 21701

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- 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.

Received for publication, May 12, 2004 , and in revised form, October 5, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Fig. S1.

Supported by a partial grant from the National Cancer Institute and by a Royal Golden Jubilee Ph.D. Scholarship from the Thailand Research Fund. This work was carried out in partial fulfillment of the requirements for the Ph.D. degree from the Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand. Current address: Dept. of Pharmacology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.

^¶ Current address: Dept. of Pharmacology, School of Pharmacy, Hoshi University, Tokyo 142-8501, Japan.

To whom correspondence should be addressed: Bldg. 37, Rm. 3112B, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892. Tel.: 301-496-0958; Fax: 301-496-8419; E-mail: shioko{at}helix.nih.gov.

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