Uteroglobin-related protein 1 (UGRP1) was originally identified as a downstream target gene for the homeodomain transcription factor T/EBP (thyroid-specific enhancer binding protein). UGRP1 is a homodimeric secretory protein of approximately 10 kDa that is highly expressed in epithelial cells of the trachea, bronchus and bronchioles. UGRP1 is a member of the secretoglobin (SCGB) gene superfamily, thus also named SCGB3A2. We hypothesized that UGRP1 may function in the regulation of local immune response in the lung based on the following reasons; 1) chromosome localization of the human UGRP1 gene at 5q31-q32, a region where an asthma susceptibility locus has been assigned, 2) similarity of UGRP1 amino acid sequence to the Uteroglobin/Clara cell secretory protein, which is known to function as an anti-inflammatory agent, 3) a polymorphism (G/A) identified in the human UGRP1 gene promoter that is associated with an increased risk of asthma, and 4) decreased Ugrp1 mRNA level found in inflamed mouse lungs. In attempt to understand the possible anti-inflammatory role of UGRP1, we found that UGRP1 gene expression is induced by IL-10, known anti-inflammatory cytokine, in human lung NCI-H441 cells at the transcriptional level. Two T/EBP binding sites located in the UGRP1 gene promoter is responsible for IL-10 induction of the UGRP1 gene. Surprisingly, STAT3, a major latent transcription factor involved in the IL-10 signaling pathway did not seem to play a role in UGRP1 gene induction. In vivo experiments using mouse lungs revealed an increase in pulmonary expression of Ugrp1 mRNA by intranasal treatment of mice with IL-10. Further, embryonic lung organ culture demonstrated the increased expression of UGRP1 in the epithelial cells of cultured lungs upon IL-10 treatment. These results demonstrate that IL-10 induces UGRP1 gene expression in lung epithelial cells through a novel T/EBP-dependent, STAT3-independent pathway, and further suggest that UGRP1 signaling pathway may play a role in anti-inflammatory activities of IL-10. Studies are in progress to understand the mechanism of T/EBP-dependent IL-10 signaling pathway. Another member of the SCGB gene superfamily, SCGB3A1 (UGRP2), closely related to UGRP1 in terms of amino acid sequence, has also been hypothesized to be involved in lung inflammation. The expression of UGRP2 was found to be induced by IL-4 and IL-13 in mtCC cells that are derived from lung Clara cells of transgenic mice expressing the SV40 large T antigen. The detailed analysis on the mechanism of UGRP2 gene induction by IL-4 and 13 is in progress.
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