Role of early growth response-1 (Egr-1) in interleukin-13-induced inflammation and remodeling

J Biol Chem. 2006 Mar 24;281(12):8161-8. doi: 10.1074/jbc.M506770200. Epub 2006 Jan 26.

Abstract

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-1alpha/CCL-3, MIP-1beta/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-beta1 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bronchoalveolar Lavage
  • Caspases / metabolism
  • Cell Death
  • Collagen / metabolism
  • DNA / chemistry
  • DNA / metabolism
  • Early Growth Response Protein 1 / metabolism
  • Early Growth Response Protein 1 / physiology*
  • Enzyme Inhibitors / pharmacology
  • Fibrosis / metabolism
  • Flavonoids / pharmacology
  • Immunoblotting
  • In Situ Nick-End Labeling
  • Inflammation
  • Interleukin-13 / genetics
  • Interleukin-13 / metabolism*
  • Lung / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Models, Biological
  • Models, Statistical
  • RNA / chemistry
  • RNA, Messenger / metabolism
  • STAT6 Transcription Factor / metabolism
  • Th2 Cells
  • Time Factors
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta1
  • Transgenes

Substances

  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Enzyme Inhibitors
  • Flavonoids
  • Interleukin-13
  • RNA, Messenger
  • STAT6 Transcription Factor
  • TGFB1 protein, human
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • RNA
  • Collagen
  • DNA
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Caspases
  • Matrix Metalloproteinase 9
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one