title: Role of early growth response-1 (Egr-1) in interleukin-13-induced inflammation and remodeling.
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.
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Cho
authors.forename: Min Jong
authors.initials: MJ
authors.lastname: Kang
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.forename: Hye Ryun
authors.initials: HR
authors.lastname: Kang
authors.forename: Xuchen
authors.initials: X
authors.lastname: Zhang
authors.forename: Patty J
authors.initials: PJ
authors.lastname: Lee
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
authors.forename: Chun Geun
authors.initials: CG
authors.lastname: Lee
mesh_terms: D000818:Animals; D018893:Bronchoalveolar Lavage; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D003094:Collagen / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D007249:Inflammation; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D015233:Models, Statistical; D012313:RNA / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D018418:Th2 Cells; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D019076:Transgenes
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D004791:Enzyme Inhibitors; D005419:Flavonoids; D018793:Interleukin-13; D012333:RNA, Messenger; D050800:STAT6 Transcription Factor; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D012313:RNA; D003094:Collagen; D004247:DNA; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020169:Caspases; D020780:Matrix Metalloproteinase 9; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one