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J. Biol. Chem., Vol. 281, Issue 12, 8161-8168, March 24, 2006
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Role of Early Growth Response-1 (Egr-1) in Interleukin-13-induced Inflammation and Remodeling*
1
From the
Section of Pulmonary and Critical Care Medicine, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520
IL-13 is an important stimulator of inflammation and tissue remodeling at sites of Th2 inflammation, which plays a key role in the pathogenesis of a variety of human disorders. We hypothesized that the ubiquitous transcription factor, early growth response-1 (Egr-1), plays a key role in IL-13-induced tissue responses. To test this hypothesis we compared the expression of Egr-1 and related moieties in lungs from wild type mice and transgenic mice in which IL-13 was overexpressed in a lung-specific fashion. We simultaneously characterized the effects of a null mutation of Egr-1 on the tissue effects of transgenic IL-13. These studies demonstrate that IL-13 stimulates Egr-1 via an Erk1/2-independent Stat6-dependent pathway(s). They also demonstrate that IL-13 is a potent stimulator of eosinophil- and mononuclear cell-rich inflammation, alveolar remodeling, and tissue fibrosis in mice with wild type Egr-1 loci and that these alterations are ameliorated in the absence of Egr-1. Lastly, they provide insights into the mechanisms of these processes by demonstrating that IL-13 stimulates select CC and CXC chemokines (MIP-1
/CCL-3, MIP-1
/CCL-4, MIP-2/CXCL2/3, MCP-1/CCL-2, MCP-2/CCL-8, MCP-3/CCL-7, MCP-5/CCL-12, KC/CXCL-1, and Lix/CXCL-5), matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and apoptosis regulators (caspase-3, -6, -8, and -9 and Bax) and activates transforming growth factor-1 and pulmonary caspases via Egr-1-dependent pathways. These studies demonstrate that Egr-1 plays a key role in the pathogenesis of IL-13-induced inflammatory and remodeling responses.
Received for publication, June 22, 2005 , and in revised form, January 20, 2006.
* This work was supported in part by the National Institutes of Health Grants HL-64242, HL-78744, HL-66571, and HL-56389 (to J. A. E.). 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.
The on-line version of this article (available at http://www.jbc.org) contains supplemental material.
1 Supported by Research Grant C-04-016 from the American Thoracic Society. To whom correspondence should be addressed: Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 300 Cedar St. (S425A), New Haven, CT 06520-8057. Tel.: 203-737-1232; Fax: 203-785-3826; E-mail: chungeun.lee{at}yale.edu.
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