International Immunology, Vol. 13, No. 2, 241-248,
February 2001
© 2001 Japanese Society for Immunology
Decreased immediate inflammatory gene induction in activating transcription factor-2 mutant mice
Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390-8884, USA
1 Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, 651 Huntington Avenue, Boston, MA 02115, USA
2 Department of Medicine, University of Massachusetts, Worcester, MA 01655, USA
Correspondence to: Correspondence to: L. Glimcher
Transcription factor activating transcription factor (ATF)-2 is activated by inflammatory signals transduced by the JNK and p38 MAP kinase pathways. To better define the role of ATF-2 in inflammation, adult mice expressing small amounts of a mutant ATF-2 protein were challenged with lipopolysaccharide (LPS), anti-CD3 antibody or virus. Within 3 h of challenge by LPS, ATF-2 mutant mice had decreased induction of the adhesion molecules E-selectin, P-selectin and VCAM-1 as well as the cytokines tumor necrosis factor-
, IL-1ß and IL-6 compared with control mice. Stimulation of T lymphocytes by anti-CD3 antibody also showed less induction of IL-1 and IL-6 in ATF-2 mutant tissues. ATF-2 mutant thymocytes treated with anti-CD3 antibody in vitro demonstrated reduced induction of c-Jun, JunB, JunD and Fra-2. However, similar to what was observed after p38 kinase inhibition in normal mice, relative ATF-2 deficiency did not prevent the development of a mononuclear cell infiltrate in the week following an inflammatory stimulus. ATF-2 mutant mice proved more susceptible to death than control mice from LPS plus D-galactosamine injection or Coxsackievirus B3 infection and had a higher incidence of mononuclear pulmonary infiltrates after exposure to Herpes simplex virus-1. ATF-2 is essential for maximal immediate induction of adhesion molecules and cytokine genes, but at later time points may even protect against overactive immune responses.
Keywords: cytokines, gene regulation, inflammation, in vivo animal models, transcription factors
Transmitting editor: A. Singer
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