Role of early growth response-1 (Egr-1) in interleukin-13-induced inflammation and remodeling.
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.
Cho
Soo Jung
SJ
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Kang
Min Jong
MJ
Homer
Robert J
RJ
Kang
Hye Ryun
HR
Zhang
Xuchen
X
Lee
Patty J
PJ
Elias
Jack A
JA
Lee
Chun Geun
CG
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
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