Abstract
Suppressor of cytokine signaling (SOCS)-1 is a critical regulator of lipopolysaccharide (LPS) tolerance and LPS-induced cytokine production. The mechanisms regulating the transcription of SOCS-1 in response to LPS are not entirely understood. Functional analysis of the SOCS-1 promoter demonstrates that early growth response-1 (Egr-1) is an important transcriptional regulator of SOCS-1. Two Egr-1 binding sites are present within the SOCS-1 promoter as shown by EMSA and supershift analysis. Further, mutation of the Egr-1 binding sites significantly reduces both the basal and LPS-induced transcriptional activity of the promoter. Chromatin immunoprecipitation experiments confirm LPS-induced binding of Egr-1 to the SOCS-1 promoter in vivo. Additionally, Egr-1(-/-) macrophages show reduced levels of LPS-induced SOCS-1 expression in comparison with macrophages derived from Egr-1(+/+) littermate controls. These results demonstrate an important role for Egr-1 in regulating both the basal and LPS-induced activity of the SOCS-1 promoter.
Highlights
The Toll-like receptor (TLR)1 family is a diverse group of transmembrane receptors that recognize microbial products called pathogen-associated molecular patterns
Previous evidence has suggested that the regulation is dependent upon autocrine and paracrine cytokine signaling mechanisms, whereby the treatment of macrophages with LPS induces cytokines such as IFN-␣/ to upregulate Suppressor of cytokine signaling (SOCS)-1 expression [19, 20]
To determine the transcriptional elements required for regulation of SOCS-1 in response to LPS, promoter constructs were cloned using DNA isolated from a human cell line
Summary
The Toll-like receptor (TLR)1 family is a diverse group of transmembrane receptors that recognize microbial products called pathogen-associated molecular patterns. These results demonstrate an important role for Egr-1 in regulating both the basal and LPS-induced activity of the SOCS-1 promoter.
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