Hepatocytes Contribute to Soluble CD14 Production, and CD14 Expression Is Differentially Regulated in Hepatocytes and Monocytes

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. 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. lipopolysaccharide enzyme-linked immunosorbent assay kilobase pair(s) glyceraldehyde-3-phosphate dehydrogenase lipopolysaccharide-binding protein Toll-like receptor Every year septic shock promoted by Gram-negative bacteria causes over 100,000 deaths in the United States (1Parrillo J.E. N. Engl. J. Med. 1993; 328: 1471-1477Crossref PubMed Scopus (1500) Google Scholar, 2Stone R. Science. 1994; 264: 365-367Crossref PubMed Scopus (126) Google Scholar). Lipopolysaccharide (LPS),1 an endotoxin of Gram-negative bacteria, is known to be responsible for initiating host responses leading to septic shock (3Glauser M.P. Zanetti G. Baumgartner J.D. Cohen J. Lancet. 1991; 338: 732-736Abstract PubMed Scopus (656) Google Scholar). LPS stimulates its response by inducing the host cells to produce and release endogenous mediators including the proinflammatory cytokines interleukin-1, interleukin-6, and tumor necrosis factor-α (4Schletter J. Heine H. Ulmer A.J. Rietschel E.T. Arch. Microbiol. 1995; 164: 383-389Crossref PubMed Scopus (265) Google Scholar). Lipopolysaccharide-binding protein (LBP), CD14, and Toll-like receptors (TLRs) are mediators of LPS stimulation (5Wright S.D. Ramos R.A. Tobias P.S. Ulevitch R.J. Mathison J.C. Science. 1990; 249: 1431-1433Crossref PubMed Scopus (3376) Google Scholar, 6Tobias P.S. Soldau K. Ulevitch R.J. J. Exp. Med. 1986; 164: 777-793Crossref PubMed Scopus (419) Google Scholar, 7Schumann R.R. Leong S.R. Flaggs G.W. Gray P.W. Wright S.D. Mathison J.C. Tobias P.S. Ulevitch R.J. Science. 1990; 249: 1429-1431Crossref PubMed Scopus (1367) Google Scholar, 8Kirschning C.J. Wesche H. Merrill A.T. Rothe M. J. Exp. Med. 1998; 188: 2091-2097Crossref PubMed Scopus (654) Google Scholar, 9Hoffmann J.A. Kafatos F.C. Janeway C.A. Ezekowitz R.A. Science. 1999; 284: 1313-1318Crossref PubMed Scopus (2137) Google Scholar, 10Wright S.D. J. Exp. Med. 1999; 189: 605-609Crossref PubMed Scopus (206) Google Scholar). There are two forms of CD14. One is the glycosylphosphatidylinositol-anchored membrane CD14 (mCD14) found mainly on the surface of cells of myeloid lineage. The other is soluble CD14 (sCD14), found in the serum and urine (11Ziegler-Heitbrock H.W. Ulevitch R.J. Immunol. Today. 1993; 14: 121-125Abstract Full Text PDF PubMed Scopus (492) Google Scholar, 12Bazil V. Baudys M. Hilgert I. Stefanova I. Low M.G. Zbrozek J. Horejsi V. Mol. Immunol. 1989; 26: 657-662Crossref PubMed Scopus (116) Google Scholar). LPS binds to CD14 in the presence of an acute phase response protein LBP. This complex mediates sepsis through TLRs. The role of CD14, LBP, and TLRs in LPS signaling has been well supported by studies in animal models (13Haziot A. Ferrero E. Kontgen F. Hijiya N. Yamamoto S. Silver J. Stewart C.L. Goyert S.M. Immunity. 1996; 4: 407-414Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar, 14Jack R.S. Fan X. Bernheiden M. Rune G. Ehlers M. Weber A. Kirsch G. Mentel R. Furll B. Freudenberg M. Schmitz G. Stelter F. Schutt C. Nature. 1997; 389: 742-745Crossref PubMed Scopus (297) Google Scholar, 15Wurfel M.M. Monks B.G. Ingalls R.R. Dedrick R.L. Delude R. Zhou D. Lamping N. Schumann R.R. Thieringer R. Fenton M.J. Wright S.D. Golenbock D. J. Exp. Med. 1997; 186: 2051-2056Crossref PubMed Scopus (148) Google Scholar, 16Poltorak A. He X. Smirnova I. Liu M.Y. Huffel C.V. Du X. Birdwell D. Alejos E. Silva M. Galanos C. Freudenberg M. Ricciardi-Castagnoli P. Layton B. Beutler B. Science. 1998; 282: 2085-2088Crossref PubMed Scopus (6382) Google Scholar). Besides its function in endotoxin signaling, it has been proposed that CD14 is involved in transportation of other lipids (17Yu B. Hailman E. Wright S.D. J. Clin. Invest. 1997; 99: 315-324Crossref PubMed Scopus (199) Google Scholar, 18Wang P.Y. Kitchens R.L. Munford R.S. J. Biol. Chem. 1998; 273: 24309-24313Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar), cell-cell interaction during different immune responses (19Lue K.H. Lauener R.P. Winchester R.J. Geha R.S. Vercelli D. J. Immunol. 1991; 147: 1134-1138PubMed Google Scholar, 20Beekhuizen H. Blokland I. Corsel-van Tilburg A.J. Koning F. van Furth R. J. Immunol. 1991; 147: 3761-3767PubMed Google Scholar, 21Asea A. Kraeft S.K. Kurt-Jones S.K. Med. PubMed Scopus Google Scholar), and of cells S. M. C. P. A. J. Immunol. 1997; Google Scholar, A. C. J.D. Nature. 1998; PubMed Scopus Google Scholar). CD14 an to in is highly expressed on the surface of monocytes/macrophages and during the of cells monocytes J.D. J. J. Clin. Invest. PubMed Scopus Google Scholar, S.M. Ferrero E. F. Science. PubMed Scopus Google Scholar, S. A. B. 1989; PubMed Google Scholar). CD14 has been as a for monocytes/macrophages. CD14 as an excellent for the of gene and have that CD14 expression the of C.J. S. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, C.J. J. Immunol. 1994; Google Scholar). Furthermore, two and critical in the of the CD14 C.J. S. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, C. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). an human CD14 genomic DNA fragment in transgenic animal we have that fragment critical regulatory which direct CD14 gene expression in the C.J. F. P. J. J. Immunol. 1999; Google Scholar). In addition, we discovered the expression of human CD14 in the of human CD14 transgenic mice as well as in human liver and lines C.J. F. P. J. J. Immunol. 1999; Google Scholar). These have been further supported by a report by K. J. 1999; Full Text Full Text PDF PubMed Scopus (73) Google that from human liver have CD14 further the of CD14 gene we transgenic mice with two genomic which the human CD14 One is and the other is in are within the CD14 fragment. Data from multiple transgenic lines that the expression of human CD14 is regulated in and The 24-kb fragment not show human CD14 expression in transgenic mice. The 33-kb fragment not show human CD14 expression in but a of CD14 expression in a and manner in the of transgenic mice. and we to a regulatory element for CD14 expression in hepatocytes. we that the liver is one of the major of soluble CD14 CD14 is expressed in cells during and has been as a for to the expression of CD14 in the in to myeloid However, in the of transgenic mice and with human and we have a human CD14 expression in cells and in C.J. F. P. J. J. Immunol. 1999; Google Scholar). 24- and 33-kb CD14 genomic DNA in studies in transgenic we have further the of CD14 expression in and The data that the 24-kb DNA fragment regulatory to CD14 The within the 33-kb but beyond the 24-kb is for CD14 expression in a and manner in and CD14 expression further genomic beyond the 33-kb fragment. and we have identified a DNA fragment within the 33-kb genomic which functions as a regulatory we have an animal which human CD14 expression in the liver but not the is to that the critical CD14 are and C.J. S. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, C. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). is a expressed J.D. Mol. Biol. 1991; PubMed Scopus Google Scholar). with as to and with to gene expression G. R. 1993; Full Text PDF PubMed Scopus Google Scholar). are a of J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). of the are expressed in a and are expressed during and acute phase and are highly expressed in and myeloid cells P. PubMed Google Scholar). with or have shown in the or function of cells P. C.J. S. A. 1997; PubMed Scopus Google Scholar, S. K. M. N. H. S. N. 1995; Full Text PDF PubMed Scopus Google Scholar, I. P. A. E. D. C. S. D. G. J. 1995; 14: PubMed Scopus Google Scholar). and monocytes the of and the CD14 upstream region as The different of expression in two on further upstream regulatory identified by a and upstream from the human CD14 in a a and a show that a including two the CD14 in hepatocytes, but not in cells and This the of regulatory which is with the results from transgenic mice. This that human CD14 expression in the liver is to its expression in of cells from the liver shown in the of upstream fragment has an further the of we containing two in and in the The fragment the as fragment. The fragment has the in the and a but in the These results that a is within the DNA fragment. Furthermore, a regulatory element function as an for an CD14 regulatory in by the of results in transgenic we found that human CD14 is highly expressed in the liver C.J. F. P. J. J. Immunol. 1999; Google Scholar). These results regulated CD14 expression in the two have to the for studies regulated CD14 expression in the R. van B. Lancet. 1991; PubMed Scopus Google in that CD14 expression be on the surface of in liver but not on the and C. Ulevitch R.J. J. Exp. Med. 1995; PubMed Scopus Google CD14 expression in liver LPS studies with and human and lines CD14 expression and by LPS S. R.A. Liu K. Goyert S.M. 1998; PubMed Google Scholar, A. H. S. J. 1999; PubMed Scopus Google Scholar). the liver is the major involved in acute phase response and CD14 is responsible for the of the endotoxin it is to the of liver CD14 expression in LPS signaling and CD14 function during LPS The generation of transgenic mice a animal system for the 33-kb transgenic human CD14 is highly expressed in the but not in soluble CD14 are in transgenic mice. human CD14 expression is in the and its expression in the liver is and liver is the other This that the expression of human CD14 in the liver soluble CD14. importantly, for the in that the liver is one of the major of soluble CD14 in The soluble CD14 in the serum of human is which a of the LPS in septic shock (17Yu B. Hailman E. Wright S.D. J. Clin. Invest. 1997; 99: 315-324Crossref PubMed Scopus (199) Google Scholar). This that soluble CD14 have other functions its function in LPS and soluble forms of CD14 have been as (17Yu B. Hailman E. Wright S.D. J. Clin. Invest. 1997; 99: 315-324Crossref PubMed Scopus (199) Google Scholar, 18Wang P.Y. Kitchens R.L. Munford R.S. J. Biol. Chem. 1998; 273: 24309-24313Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). of soluble CD14 in serum is in human serum A. K. S. C. Ulevitch R. R. J. Immunol. 1999; Google Scholar). have transgenic which express different of soluble CD14. of transgenic lines have soluble human CD14 expression the to CD14 in human be models for CD14 Every year septic shock promoted by Gram-negative bacteria causes over 100,000 deaths in the United States (1Parrillo J.E. N. Engl. J. Med. 1993; 328: 1471-1477Crossref PubMed Scopus (1500) Google Scholar, 2Stone R. Science. 1994; 264: 365-367Crossref PubMed Scopus (126) Google Scholar). Lipopolysaccharide (LPS),1 an endotoxin of Gram-negative bacteria, is known to be responsible for initiating host responses leading to septic shock (3Glauser M.P. Zanetti G. Baumgartner J.D. Cohen J. Lancet. 1991; 338: 732-736Abstract PubMed Scopus (656) Google Scholar). LPS stimulates its response by inducing the host cells to produce and release endogenous mediators including the proinflammatory cytokines interleukin-1, interleukin-6, and tumor necrosis factor-α (4Schletter J. Heine H. Ulmer A.J. Rietschel E.T. Arch. Microbiol. 1995; 164: 383-389Crossref PubMed Scopus (265) Google Scholar). Lipopolysaccharide-binding protein (LBP), CD14, and Toll-like receptors (TLRs) are mediators of LPS stimulation (5Wright S.D. Ramos R.A. Tobias P.S. Ulevitch R.J. Mathison J.C. Science. 1990; 249: 1431-1433Crossref PubMed Scopus (3376) Google Scholar, 6Tobias P.S. Soldau K. Ulevitch R.J. J. Exp. Med. 1986; 164: 777-793Crossref PubMed Scopus (419) Google Scholar, 7Schumann R.R. Leong S.R. Flaggs G.W. Gray P.W. Wright S.D. Mathison J.C. Tobias P.S. Ulevitch R.J. Science. 1990; 249: 1429-1431Crossref PubMed Scopus (1367) Google Scholar, 8Kirschning C.J. Wesche H. Merrill A.T. Rothe M. J. Exp. Med. 1998; 188: 2091-2097Crossref PubMed Scopus (654) Google Scholar, 9Hoffmann J.A. Kafatos F.C. Janeway C.A. Ezekowitz R.A. Science. 1999; 284: 1313-1318Crossref PubMed Scopus (2137) Google Scholar, 10Wright S.D. J. Exp. Med. 1999; 189: 605-609Crossref PubMed Scopus (206) Google Scholar). There are two forms of CD14. One is the glycosylphosphatidylinositol-anchored membrane CD14 (mCD14) found mainly on the surface of cells of myeloid lineage. The other is soluble CD14 (sCD14), found in the serum and urine (11Ziegler-Heitbrock H.W. Ulevitch R.J. Immunol. Today. 1993; 14: 121-125Abstract Full Text PDF PubMed Scopus (492) Google Scholar, 12Bazil V. Baudys M. Hilgert I. Stefanova I. Low M.G. Zbrozek J. Horejsi V. Mol. Immunol. 1989; 26: 657-662Crossref PubMed Scopus (116) Google Scholar). LPS binds to CD14 in the presence of an acute phase response protein LBP. This complex mediates sepsis through TLRs. The role of CD14, LBP, and TLRs in LPS signaling has been well supported by studies in animal models (13Haziot A. Ferrero E. Kontgen F. Hijiya N. Yamamoto S. Silver J. Stewart C.L. Goyert S.M. Immunity. 1996; 4: 407-414Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar, 14Jack R.S. Fan X. Bernheiden M. Rune G. Ehlers M. Weber A. Kirsch G. Mentel R. Furll B. Freudenberg M. Schmitz G. Stelter F. Schutt C. Nature. 1997; 389: 742-745Crossref PubMed Scopus (297) Google Scholar, 15Wurfel M.M. Monks B.G. Ingalls R.R. Dedrick R.L. Delude R. Zhou D. Lamping N. Schumann R.R. Thieringer R. Fenton M.J. Wright S.D. Golenbock D. J. Exp. Med. 1997; 186: 2051-2056Crossref PubMed Scopus (148) Google Scholar, 16Poltorak A. He X. Smirnova I. Liu M.Y. Huffel C.V. Du X. Birdwell D. Alejos E. Silva M. Galanos C. Freudenberg M. Ricciardi-Castagnoli P. Layton B. Beutler B. Science. 1998; 282: 2085-2088Crossref PubMed Scopus (6382) Google Scholar). Besides its function in endotoxin signaling, it has been proposed that CD14 is involved in transportation of other lipids (17Yu B. Hailman E. Wright S.D. J. Clin. Invest. 1997; 99: 315-324Crossref PubMed Scopus (199) Google Scholar, 18Wang P.Y. Kitchens R.L. Munford R.S. J. Biol. Chem. 1998; 273: 24309-24313Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar), cell-cell interaction during different immune responses (19Lue K.H. Lauener R.P. Winchester R.J. Geha R.S. Vercelli D. J. Immunol. 1991; 147: 1134-1138PubMed Google Scholar, 20Beekhuizen H. Blokland I. Corsel-van Tilburg A.J. Koning F. van Furth R. J. Immunol. 1991; 147: 3761-3767PubMed Google Scholar, 21Asea A. Kraeft S.K. Kurt-Jones S.K. Med. PubMed Scopus Google Scholar), and of cells S. M. C. P. A. J. Immunol. 1997; Google Scholar, A. C. J.D. Nature. 1998; PubMed Scopus Google Scholar). CD14 an to in CD14 is highly expressed on the surface of monocytes/macrophages and during the of cells monocytes J.D. J. J. Clin. Invest. PubMed Scopus Google Scholar, S.M. Ferrero E. F. Science. PubMed Scopus Google Scholar, S. A. B. 1989; PubMed Google Scholar). CD14 has been as a for monocytes/macrophages. CD14 as an excellent for the of gene and have that CD14 expression the of C.J. S. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, C.J. J. Immunol. 1994; Google Scholar). Furthermore, two and critical in the of the CD14 C.J. S. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, C. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). an human CD14 genomic DNA fragment in transgenic animal we have that fragment critical regulatory which direct CD14 gene expression in the C.J. F. P. J. J. Immunol. 1999; Google Scholar). In addition, we discovered the expression of human CD14 in the of human CD14 transgenic mice as well as in human liver and lines C.J. F. P. J. J. Immunol. 1999; Google Scholar). These have been further supported by a report by K. J. 1999; Full Text Full Text PDF PubMed Scopus (73) Google that from human liver have CD14 further the of CD14 gene we transgenic mice with two genomic which the human CD14 One is and the other is in are within the CD14 fragment. Data from multiple transgenic lines that the expression of human CD14 is regulated in and The 24-kb fragment not show human CD14 expression in transgenic mice. The 33-kb fragment not show human CD14 expression in but a of CD14 expression in a and manner in the of transgenic mice. and we to a regulatory element for CD14 expression in hepatocytes. we that the liver is one of the major of soluble CD14 CD14 is expressed in cells during and has been as a for to the expression of CD14 in the in to myeloid However, in the of transgenic mice and with human and we have a human CD14 expression in cells and in C.J. F. P. J. J. Immunol. 1999; Google Scholar). 24- and 33-kb CD14 genomic DNA in studies in transgenic we have further the of CD14 expression in and The data that the 24-kb DNA fragment regulatory to CD14 The within the 33-kb but beyond the 24-kb is for CD14 expression in a and manner in and CD14 expression further genomic beyond the 33-kb fragment. and we have identified a DNA fragment within the 33-kb genomic which functions as a regulatory we have an animal which human CD14 expression in the liver but not the is to that the critical CD14 are and C.J. S. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, C. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). is a expressed J.D. Mol. Biol. 1991; PubMed Scopus Google Scholar). with as to and with to gene expression G. R. 1993; Full Text PDF PubMed Scopus Google Scholar). are a of J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). of the are expressed in a and are expressed during and acute phase and are highly expressed in and myeloid cells P. PubMed Google Scholar). with or have shown in the or function of cells P. C.J. S. A. 1997; PubMed Scopus Google Scholar, S. K. M. N. H. S. N. 1995; Full Text PDF PubMed Scopus Google Scholar, I. P. A. E. D. C. S. D. G. J. 1995; 14: PubMed Scopus Google Scholar). and monocytes the of and the CD14 upstream region as The different of expression in two on further upstream regulatory identified by a and upstream from the human CD14 in a a and a show that a including two the CD14 in hepatocytes, but not in cells and This the of regulatory which is with the results from transgenic mice. This that human CD14 expression in the liver is to its expression in of cells from the liver shown in the of upstream fragment has an further the of we containing two in and in the The fragment the as fragment. The fragment has the in the and a but in the These results that a is within the DNA fragment. Furthermore, a regulatory element function as an for an CD14 regulatory in by the of results in transgenic we found that human CD14 is highly expressed in the liver C.J. F. P. J. J. Immunol. 1999; Google Scholar). These results regulated CD14 expression in the two have to the for studies regulated CD14 expression in the R. van B. Lancet. 1991; PubMed Scopus Google in that CD14 expression be on the surface of in liver but not on the and C. Ulevitch R.J. J. Exp. Med. 1995; PubMed Scopus Google CD14 expression in liver LPS studies with and human and lines CD14 expression and by LPS S. R.A. Liu K. Goyert S.M. 1998; PubMed Google Scholar, A. H. S. J. 1999; PubMed Scopus Google Scholar). the liver is the major involved in acute phase response and CD14 is responsible for the of the endotoxin it is to the of liver CD14 expression in LPS signaling and CD14 function during LPS The generation of transgenic mice a animal system for the 33-kb transgenic human CD14 is highly expressed in the but not in soluble CD14 are in transgenic mice. human CD14 expression is in the and its expression in the liver is and liver is the other This that the expression of human CD14 in the liver soluble CD14. importantly, for the in that the liver is one of the major of soluble CD14 in The soluble CD14 in the serum of human is which a of the LPS in septic shock (17Yu B. Hailman E. Wright S.D. J. Clin. Invest. 1997; 99: 315-324Crossref PubMed Scopus (199) Google Scholar). This that soluble CD14 have other functions its function in LPS and soluble forms of CD14 have been as (17Yu B. Hailman E. Wright S.D. J. Clin. Invest. 1997; 99: 315-324Crossref PubMed Scopus (199) Google Scholar, 18Wang P.Y. Kitchens R.L. Munford R.S. J. Biol. Chem. 1998; 273: 24309-24313Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). of soluble CD14 in serum is in human serum A. K. S. C. Ulevitch R. R. J. Immunol. 1999; Google Scholar). have transgenic which express different of soluble CD14. of transgenic lines have soluble human CD14 expression the to CD14 in human be models for CD14 CD14 is expressed in cells during and has been as a for to the expression of CD14 in the in to myeloid However, in the of transgenic mice and with human and we have a human CD14 expression in cells and in C.J. F. P. J. J. Immunol. 1999; Google Scholar). 24- and 33-kb CD14 genomic DNA in studies in transgenic we have further the of CD14 expression in and The data that the 24-kb DNA fragment regulatory to CD14 The within the 33-kb but beyond the 24-kb is for CD14 expression in a and manner in and CD14 expression further genomic beyond the 33-kb fragment. and we have identified a DNA fragment within the 33-kb genomic which functions as a regulatory we have an animal which human CD14 expression in the liver but not the is to that the critical CD14 are and C.J. S. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, C. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). is a expressed J.D. Mol. Biol. 1991; PubMed Scopus Google Scholar). with as to and with to gene expression G. R. 1993; Full Text PDF PubMed Scopus Google Scholar). are a of J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). of the are expressed in a and are expressed during and acute phase and are highly expressed in and myeloid cells P. PubMed Google Scholar). with or have shown in the or function of cells P. C.J. S. A. 1997; PubMed Scopus Google Scholar, S. K. M. N. H. S. N. 1995; Full Text PDF PubMed Scopus Google Scholar, I. P. A. E. D. C. S. D. G. J. 1995; 14: PubMed Scopus Google Scholar). and monocytes the of and the CD14 upstream region as The different of expression in two on further upstream regulatory identified by a and upstream from the human CD14 in a a and a show that a including two the CD14 in hepatocytes, but not in cells and This the of regulatory which is with the results from transgenic mice. This that human CD14 expression in the liver is to its expression in of cells from the liver shown in the of upstream fragment has an further the of we containing two in and in the The fragment the as fragment. The fragment has the in the and a but in the These results that a is within the DNA fragment. Furthermore, a regulatory element function as an for an CD14 regulatory in hepatocytes. by the of results in transgenic we found that human CD14 is highly expressed in the liver C.J. F. P. J. J. Immunol. 1999; Google Scholar). These results regulated CD14 expression in the two have to the for studies regulated CD14 expression in the R. van B. Lancet. 1991; PubMed Scopus Google in that CD14 expression be on the surface of in liver but not on the and C. Ulevitch R.J. J. Exp. Med. 1995; PubMed Scopus Google CD14 expression in liver LPS studies with and human and lines CD14 expression and by LPS S. R.A. Liu K. Goyert S.M. 1998; PubMed Google Scholar, A. H. S. J. 1999; PubMed Scopus Google Scholar). the liver is the major involved in acute phase response and CD14 is responsible for the of the endotoxin it is to the of liver CD14 expression in LPS signaling and CD14 function during LPS The generation of transgenic mice a animal system for In the 33-kb transgenic human CD14 is highly expressed in the but not in soluble CD14 are in transgenic mice. human CD14 expression is in the and its expression in the liver is and liver is the other This that the expression of human CD14 in the liver soluble CD14. importantly, for the in that the liver is one of the major of soluble CD14 in The soluble CD14 in the serum of human is which a of the LPS in septic shock (17Yu B. Hailman E. Wright S.D. J. Clin. Invest. 1997; 99: 315-324Crossref PubMed Scopus (199) Google Scholar). This that soluble CD14 have other functions its function in LPS and soluble forms of CD14 have been as (17Yu B. Hailman E. Wright S.D. J. Clin. Invest. 1997; 99: 315-324Crossref PubMed Scopus (199) Google Scholar, 18Wang P.Y. Kitchens R.L. Munford R.S. J. Biol. Chem. 1998; 273: 24309-24313Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). of soluble CD14 in serum is in human serum A. K. S. C. Ulevitch R. R. J. Immunol. 1999; Google Scholar). have transgenic which express different of soluble CD14. of transgenic lines have soluble human CD14 expression the to CD14 in human be models for CD14 H. for cells and for in transgenic mice.