Bacterial peptidoglycan-induced tnf-α transcription is mediated through the transcription factors Egr-1, Elk-1, and NF-κB

Z. Xu, Roman Dziarski, Q. Wang, K. Swartz, K. M. Sakamoto, Dipika Gupta

Research output: Contribution to journalArticle

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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-α is one of the highest induced cytokines in macrophages stimulated with PGN; however, the regulation of tnf-α 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-a gene in macrophages stimulated with PGN. Our results demonstrated that PGN-induced expression of human tnf-α 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 κB3 significantly reduced this induction. The transcription factor c-Jun bound the cAMP response element site, Egr-1 bound the Egr-1 motif, and NF-κB p50 and p65 bound to the κB3 site on the tnf-α 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-α is directly mediated through the transcription factors c-Jun, Egr-1, and NF-KB, and indirectly through the transcription factor Elk-1.

Original languageEnglish
Pages (from-to)6975-6982
Number of pages8
JournalJournal of Immunology
Volume167
Issue number12
StatePublished - Dec 15 2001

Fingerprint

Early Growth Response Protein 1
Peptidoglycan
Serum Response Element
Transcription Factors
Response Elements
Growth
ets-Domain Protein Elk-1
Proto-Oncogene Proteins c-ets
Macrophages
Serum Response Factor
Genes
Mutation
Cellular Structures
Cell Wall
Immune System

ASJC Scopus subject areas

  • Immunology

Cite this

Bacterial peptidoglycan-induced tnf-α transcription is mediated through the transcription factors Egr-1, Elk-1, and NF-κB. / Xu, Z.; Dziarski, Roman; Wang, Q.; Swartz, K.; Sakamoto, K. M.; Gupta, Dipika.

In: Journal of Immunology, Vol. 167, No. 12, 15.12.2001, p. 6975-6982.

Research output: Contribution to journalArticle

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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-α is one of the highest induced cytokines in macrophages stimulated with PGN; however, the regulation of tnf-α 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-a gene in macrophages stimulated with PGN. Our results demonstrated that PGN-induced expression of human tnf-α 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 κB3 significantly reduced this induction. The transcription factor c-Jun bound the cAMP response element site, Egr-1 bound the Egr-1 motif, and NF-κB p50 and p65 bound to the κB3 site on the tnf-α 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-α is directly mediated through the transcription factors c-Jun, Egr-1, and NF-KB, and indirectly through the transcription factor Elk-1.",
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