Rehli, M., Poltorak, A., Schwarzfischer, L., Krause, S. W., Andreesen, Reinhard and Beutler, B.
(2000)
PU.1 and interferon consensus sequence-binding protein regulate the myeloid expression of the human Toll-like receptor 4 gene.
The Journal of biological chemistry 275 (13), pp. 9773-81.
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Abstract
The protein product of the Toll-like receptor (TLR) 4 gene has been implicated in the signal transduction events induced by lipopolysaccharide (LPS). In mice, destructive mutations of Tlr4 impede the normal response to LPS and cause a high susceptibility to Gram-negative infection. Expression of TLR4 mRNA in humans is restricted to a small number of cell types, including LPS-responsive myeloid ...
Abstract
The protein product of the Toll-like receptor (TLR) 4 gene has been implicated in the signal transduction events induced by lipopolysaccharide (LPS). In mice, destructive mutations of Tlr4 impede the normal response to LPS and cause a high susceptibility to Gram-negative infection. Expression of TLR4 mRNA in humans is restricted to a small number of cell types, including LPS-responsive myeloid cells, B-cells, and endothelial cells. To investigate the molecular basis for TLR4 expression in cells of myeloid origin, we cloned the human TLR4 gene and analyzed its putative 5'-proximal promoter. In transient transfections a region of only 75 base pairs upstream of the major transcription initiation site was sufficient to induce maximal luciferase activity in THP-1 cells. The sequence of this region is similar in human and mouse TLR4 genes and lacks a TATA box, typical Sp1-sites or CCAAT box sequences. Instead, it contains consensus-binding sites for Ets family transcription factors, octamer-binding factors, and a composite interferon response factor/Ets motif. The activity of the promoter in macrophages was strictly dependent on the integrity of both half sites of the composite interferon response factor/Ets motif, which was constitutively bound by the myeloid and B-cell-specific transcription factor PU.1 and interferon consensus sequence-binding protein. These results indicate that the two tissue-restricted transcription factors PU.1 and interferon consensus sequence-binding protein participate in the basal regulation of human TLR4 in myeloid cells. Cloning of the human TLR4 gene provides a basis for further investigation of the possible impact of genetic variations on the susceptibility to infection and sepsis.
Export bibliographical data
| Item type: | Article |
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| Date: | 2000 |
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| Institutions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
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| Identification Number: | | Value | Type |
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| 10734131 | PubMed ID |
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| Classification: | | Notation | Type |
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| Amino Acid Sequence | MESH | | Animals | MESH | | Base Sequence | MESH | | Bone Marrow/metabolism | MESH | | Cloning, Molecular | MESH | | DNA | MESH | | Drosophila Proteins | MESH | | Gene Expression Regulation/physiology | MESH | | Humans | MESH | | Interferon Regulatory Factors | MESH | | Membrane Glycoproteins/genetics | MESH | | Mice | MESH | | Molecular Sequence Data | MESH | | Mutagenesis, Site-Directed | MESH | | Promoter Regions, Genetic | MESH | | Protein Binding | MESH | | Proto-Oncogene Proteins/physiology | MESH | | Receptors, Cell Surface/genetics | MESH | | Repressor Proteins/physiology | MESH | | Sequence Homology, Nucleic Acid | MESH | | Toll-Like Receptor 4 | MESH | | Toll-Like Receptors | MESH | | Trans-Activators/physiology | MESH |
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| Dewey Decimal Classification: | 600 Technology > 610 Medical sciences Medicine |
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| Status: | Published |
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| Refereed: | Yes, this version has been refereed |
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| Created at the University of Regensburg: | Yes |
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| Item ID: | 14354 |
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