Abstract
CD14 presents as a glycosylphosphatidylinositol-linked membrane protein on the surface of monocytes/macrophages and as a soluble protein in the serum. Our previous studies have shown that an 80-kilobase pair (kb) genomic DNA fragment containing the human CD14 gene is sufficient to direct CD14 expression in a monocyte-specific manner in transgenic mice. In addition, we discovered that human CD14 is highly expressed in hepatocytes. Here, we report the generation of transgenic mice with either a 24- or 33-kb human CD14 genomic DNA fragment. Data from multiple transgenic lines show that neither the 24- nor the 33-kb transgenic mice express human CD14 in monocytes/macrophages. However, human CD14 is highly expressed in the liver of the 33-kb transgenic mice. These results demonstrate that human CD14 expression is regulated differently in monocytes and hepatocytes. Furthermore, we identified an upstream regulatory element beyond the 24-kb region, but within the 33-kb region of the human CD14 gene, which is critical for CD14 expression in hepatocytes, but not in monocytes/macrophages. Most importantly, the data demonstrate that the liver is one of the major organs for the production of soluble CD14. These transgenic mice provide an excellent system to further explore the functions of soluble CD14.
Highlights
Every year septic shock promoted by Gram-negative bacteria causes over 100,000 deaths in the United States [1, 2]
We identified an upstream regulatory element beyond the 24-kb region, but within the 33-kb region of the human CD14 gene, which is critical for CD14 expression in hepatocytes, but not in monocytes/macrophages
Generation of Transgenic Mice—Previous studies have demonstrated that the Sp1 sites and C/EBP site in the proximal promoter region of the CD14 gene are critical for CD14 expression [27, 29]
Summary
Every year septic shock promoted by Gram-negative bacteria causes over 100,000 deaths in the United States [1, 2]. Using an 80-kb human CD14 genomic DNA fragment in transgenic animal studies, we have demonstrated that this fragment contains critical regulatory elements which direct CD14 gene expression in the monocytic lineage [30]. We discovered the clear expression of human CD14 in the hepatocytes of 80-kb human CD14 transgenic mice as well as in human liver tissue and hepatocytic cell lines [30]. Data collected from multiple transgenic founder lines indicated that the expression of human CD14 is differentially regulated in monocytic and hepatocytic lineages. The 33-kb fragment did not show human CD14 expression in monocytic cells, but showed a high level of CD14 expression in a copy numberdependent and position-independent manner in the livers of transgenic mice. We revealed that the liver is one of the major sources of soluble CD14 production
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