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

Z. Xu, R. Dziarski, Q. Wang, K. Swartz, K. M. Sakamoto, D. Gupta

Research output: Contribution to journalArticle

67 Scopus citations

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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