Decreased immediate inflammatory gene induction in activating transcription factor-2 mutant mice.
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-alpha, IL-1beta 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.
Reimold
A M
AM
Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390-8884, USA.
Kim
J
J
Finberg
R
R
Glimcher
L H
LH
D051698:Activating Transcription Factor 2; D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics*; D003384:Coxsackievirus Infections / Q000235:genetics / Q000276:immunology / Q000401:mortality; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D016207:Cytokines / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D029822:Enterovirus B, Human / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D006561:Herpes Simplex / Q000235:genetics / Q000276:immunology / Q000401:mortality; D018259:Herpesvirus 1, Human / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000821:virology; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics*; D015533:Transcriptional Activation
D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D015815:Cell Adhesion Molecules; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D008070:Lipopolysaccharides; D018808:Transcription Factor AP-1; D014157:Transcription Factors