Bacterial Peptidoglycan-Inducedtnf-αTranscription Is Mediated Through the Transcription Factors Egr-1, Elk-1, and NF-κB

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-α 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-κB, and indirectly through the transcription factor Elk-1.

Structure, organization and expression of common carp (Cyprinus carpio L.) NKEF-B gene

“…BR-C Z4, an ecdysone-responsive key regulator of metamorphosis during third instar stage and early prepupal development [36]. Elk-1, interacting with SRF [37], can displace myocardin from its binding site on SRF and it can activate the transcription of TNF-a, which plays an important role in the innate immune system [38]. ER mediates gene regulation in response to estrogen hormone [39].…”

Amyloid Peptide-Induced Cytokine and Chemokine Expression in THP-1 Monocytes Is Blocked by Small Inhibitory RNA Duplexes for Early Growth Response-1 Messenger RNA

“…Egr-1 is one of several target transcription factors of activated Elk-1 (43,44). The promoter regions of TNF-␣ have putative binding sites for transcription factors Egr-1, AP-1, NF-␤, and CREB (52,53).…”

“…Next, we determined whether A␤-induced activation of ERKs and Elk-1 resulted in activation of transcription factor Egr-1, because Egr-1 is a target transcription factor of activated Elk-1 (43,44). The involvement of Egr-1 in A␤-mediated induction of cytokines and chemokines is likely, since some of these cytokines and chemokine genes have Egr-1 consensus sites in their promoters (45,46).…”

Activating Transcription Factor 3-mediated Chemo-intervention with Cancer Chemokines in a Noncanonical Pathway under Endoplasmic Reticulum Stress

“…EGR-1-associated cytokine production has been examined in combination with three central proinflammatory transcription factors, NF-B, CCAAT-enhancer-binding protein, and AP-1 (activator protein 1) (46), and some of the target gene transcription occurs through synergistic interaction of EGR-1 with other transcription factors, such as nuclear factors of activated T cells, by forming heterodimers (47). Although a range of growth-or differentiation-related stimuli can promote the expression of EGR-1, bacterial products such as lipopolysaccharide and peptidoglycan also trigger EGR-1 gene expression during inflammation (48,49). EGR-1 binds to the Sp1/EGR-1 overlapping sequence motif, which is located in the promoter region of TNF-␣ (50,51).…”