The mouse UGRP gene family consists of two genes, Ugrp1 and Ugrp2. In this study, the genomic structure and expression patterns of Ugrp2 and its alternative spliced form were characterized. The authentic Ugrp2 gene has three exons and two introns, similar to the Ugrp1 gene, which produces a secreted protein. The Ugrp2 variant uses a sequence located between authentic exons 1 and 2, resulting in a cytoplasmic form due to a termination codon within the inserted sequence. Both mouse and human UGRP2 mRNAs are expressed in lung. In the case of human, the mRNA is expressed at the highest level in trachea, followed by salivary gland at a level similar to lung. Weak expression was also found in fetal lung and mammary gland. Ugrp2 was mapped by fluorescence in situ hybridization to mouse chromosome 11A5–B1 and human chromosome 5q35. These regions are known to be homologous. Interspecific mouse backcross mapping was also performed to obtain further detailed localization of mouse Ugrp1 and Ugrp2.
Airway inflammation is thought to play a major role in the pathogenesis of bronchial asthma. The precise role of individual inflammatory cells, mediator and asthma related genes in allergic lung diseases is not completely understood. The uteroglobin-related protein (UGRP) 1 was proposed to be an asthma candidate gene and play a role in regulating lung inflammation, however its precise function in the airways remains obscure. In this investigation, we used a mouse model of allergic airway inflammation to establish a relationship between UGRP 1 and IL-5 in airway inflammation. Ovalbumin (OVA) challenged mice demonstrate eosinophilia in airway tissues and high levels of IL-5 in bronchoalveolar lavage (BAL) fluid analogous to that found in bronchial asthma. Interestingly, these "OVA-challenged" mice show down-regulation of Ugrp1 expression as compared with the control group. Regression analysis further demonstrates a significant negative correlation between Ugrp1 mRNA expression in the lung and IL-5 levels in BAL fluid with r = 0.948 and P < 0.0001 when IL-5 levels were normalized by log transformation. Intranasal instillation of IL-5 to mice revealed an inhibitory effect of IL-5 on the expression of Ugrp1 mRNA. Together, these results indicate an involvement of IL-5 in the down-regulation of Ugrp1 expression in airway inflammation such as allergic asthma disease.
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. Uteroglobin-related protein 1 (UGRP1) 1 was originally identified as a downstream target gene for homeodomain transcription factor T/EBP (thyroid-specific enhancer-binding protein), also called thyroid transcription factor-1 (TTF-1) or NKX2.1 (1). T/EBP regulates the expression of thyroid-and lung-specific genes including thyroglobulin (2), thyroid peroxidase (3, 4), thyrotropin receptor (5), and Na/I symporter (6) in the thyroid, and surfactant proteins A (7), B (8), and C (9), and Clara cell secretory protein (10) in the lung. T/EBP is expressed in brain, thyroid, and lung epithelium during embryogenesis and is essential for the genesis of these organs (11). In adult lung, the expression of T/EBP is confined to both the conducting airways and type II alveolar epithelial cells (12).UGRP1, officially named Secretoglobin gene family 3A2 (13), is a novel gene encoding a homodimeric secretory protein of ϳ10 kDa that is highly expressed in epithelial cells of the trachea, bronchus, and bronchioles (1). Based on our previous results, there is considerable evidence to suggest that UGRP1 may function in the regulation of the local immune response in the lung. First, the human UGRP1 gene is located on chromosome 5q31-q32, a region where one of the asthma susceptibility genes was assigned and genes coding for several Th2-type cytokines such as interleukin (IL)-4, IL-5, and IL-13 are located (13). Second, the UGRP1 amino acid sequence exhibits similarity to the UG/Clara cell secretory protein, which is known to function as an anti-inflammatory agent via inhibition of phospholipase A 2 (1). Third, a polymorphism (G/A) was identified in the human UGRP1 gene promoter that is associated with an increased risk of asthma in a Japanese population of adult asthmatic patients (14). Lastly, the mRNA level of Ugrp1 is decreased in inflamed mouse lungs, and returns to basal levels following dexamethasone treatment (1).IL-10 is a pleiotropic cytokine that was shown to mediate anti-inflammatory, immunosuppressive, and tissue protective functions. The known IL-10 signaling is through binding to specific receptors IL-10R1 and IL-10R2, which leads to activation of the JAK-STAT (Janus kinase-signal transducers and activators of transcription) signal transduction pathways (15). An anti-inflammatory role for I...
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