Bacterial Peptidoglycan-Inducedtnf-αTranscription Is Mediated Through the Transcription Factors Egr-1, Elk-1, and NF-κB
- 15 December 2001
- journal article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 167 (12), 6975-6982
- https://doi.org/10.4049/jimmunol.167.12.6975
Abstract
Bacteria and their ubiquitous cell wall component peptidoglycan (PGN) activate the innate immune system of the host and induce the release of inflammatory molecules. TNF-alpha is one of the highest induced cytokines in macrophages stimulated with PGN; however, the regulation of tnf-alpha expression in PGN-activated cells is poorly understood. This study was done to identify some of the transcription factors that regulate the expression of the tnf-alpha gene in macrophages stimulated with PGN. Our results demonstrated that PGN-induced expression of human tnf-alpha gene is regulated by sequences proximal to -182 bp of the promoter. Mutations within the binding sites for cAMP response element, early growth response (Egr)-1, and kappaB3 significantly reduced this induction. The transcription factor c-Jun bound the cAMP response element site, Egr-1 bound the Egr-1 motif, and NF-kappaB p50 and p65 bound to the kappaB3 site on the tnf-alpha promoter. PGN rapidly induced transcription of egr-1 gene and this induction was significantly reduced by specific mutations within the serum response element-1 domain of the egr-1 promoter. PGN also induced phosphorylation and activation of Elk-1, a member of the Ets family of transcription factors. Elk-1 and serum response factor proteins bound the serum response element-1 domain on the egr-1 promoter, and PGN-induced expression of the egr-1 was inhibited by dominant-negative Elk-1. These results indicate that PGN induces activation of the transcription factors Egr-1 and Elk-1, and that PGN-induced expression of tnf-alpha is directly mediated through the transcription factors c-Jun, Egr-1, and NF-kappaB, and indirectly through the transcription factor Elk-1.Keywords
This publication has 34 references indexed in Scilit:
- Chemokines Are the Main Proinflammatory Mediators in Human Monocytes Activated by Staphylococcus aureus, Peptidoglycan, and EndotoxinPublished by Elsevier BV ,2000
- Granulocyte Colony-stimulating Factor Induces egr-1Up-regulation through Interaction of Serum Response Element-binding ProteinsPublished by Elsevier BV ,2000
- Phylogenetic Perspectives in Innate ImmunityScience, 1999
- Complex NF-κB Interactions at the Distal Tumor Necrosis Factor Promoter Region in Human MonocytesJournal of Biological Chemistry, 1998
- Lipopolysaccharide Induction of the Tumor Necrosis Factor-α Promoter in Human Monocytic CellsPublished by Elsevier BV ,1997
- AP-1 function and regulationCurrent Opinion in Cell Biology, 1997
- The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domainCell, 1993
- Transformation suppressor activity of a Jun transcription factor lacking its activation domainNature, 1991
- Endotoxin-responsive sequences control cachectin/tumor necrosis factor biosynthesis at the translational level.The Journal of Experimental Medicine, 1990
- Genetic analysis of the human tumor necrosis factor alpha/cachectin promoter region in a macrophage cell line.The Journal of Experimental Medicine, 1989