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Originally published In Press as doi:10.1074/jbc.M408938200 on November 15, 2004

J. Biol. Chem., Vol. 280, Issue 4, 2596-2605, January 28, 2005
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Early Growth Response-1 Regulates Lipopolysaccharide-induced Suppressor of Cytokine Signaling-1 Transcription*

Justin Mostecki{ddagger}, Brian M. Showalter§, and Paul B. Rothman{ddagger}§

From the {ddagger}Department of Microbiology and §Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032

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.


Received for publication, August 4, 2004 , and in revised form, October 27, 2004.

* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Medicine, Division of Pulmonary, Allergy and Critical Care, P&S Bldg., Rm. 8-425, Columbia University, 630 W. 168th St., New York, NY 10032. Tel.: 212-305-6982; Fax: 212-305-1870; E-mail: pbr3{at}columbia.edu.


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