Am. J. Respir. Crit. Care Med., Volume 163, Number 3, March 2001, 778-785

The Transcription Factor Early Growth-response Factor 1 Modulates Tumor Necrosis Factor-, Immunoglobulin E, and Airway Responsiveness in Mice

ERIC S. SILVERMAN, GEORGE T. DE SANCTIS, JOSHUA BOYCE, JAMES A. MACLEAN, AIPING JIAO, FRANCIS H. Y. GREEN, HARTMUT GRASEMANN, DOUGLAS FAUNCE, GARRET FITZMAURICE, GUO-PING SHI, JOAN STEIN-STREILEIN, JEFFREY MILBRANDT, TUCKER COLLINS, and JEFFREY M. DRAZEN

Pulmonary and Critical Care Division, Immunology and Allergy Division, Department of Medicine, Department of Pathology, Brigham and Women's Hospital, Immunology and Allergy Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts; Department of Pathology and Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; and Respiratory Research Group, University of Calgary, Calgary, Alberta, Canada

Early growth-response factor 1 (Egr-1) is a sequence-specific transcription factor that plays a regulatory role in the expression of many genes important in inflammation, cell growth, apoptosis, and the pathogenesis of disease. In vitro studies suggest that Egr-1 is capable of regulating the expression of tumor necrosis factor- (TNF-) and other genes involved in airway inflammation and reactivity following allergen stimulation. On the basis of these data, we hypothesized that in the absence of Egr-1, the TNF- response and subsequent downstream inflammatory events that usually follow allergen challenge would be diminished. To test our hypothesis Egr-1 knock-out (KO) mice were examined in an ovalbumin (OVA)-induced model of airway inflammation and reactivity, and compared with identically treated wild-type (WT) control mice. In response to OVA sensitization and airway challenge, KO mice had diminished TNF- mRNA and protein in the lungs and mast cells compared with WT mice. Interestingly, the KO mice had elevated IgE levels at baseline and after allergen challenge compared with WT mice. Furthermore, the airways of KO mice were hyporesponsive to methacholine challenge at baseline and after allergen challenge. These data indicate that Egr-1 modulates TNF-, IgE, and airway responsiveness in mice.

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