Decreased immediate inflammatory gene induction in activating transcription factor-2 mutant mice

Transcription factor activating transcription factor (ATF)-5 is activated b y inflammatory signals transduced by the JNK and p38 MAP kinase pathways. T o better define the role of ATF-P in inflammation, adult mice expressing sm all amounts of a mutant ATF-5 protein were challenged with lipopolysacchari de (LPS), anti-CD3 antibody or virus. Within 3 h of challenge by LPS, ATF-5 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-1 beta and IL-6 compared with control mice. Stimulation of T lymphocyte s by anti-CD3 antibody also showed less induction of IL-1 and IL-8 in ATF-2 mutant tissues. ATF-5 mutant thymocytes treated with anti-CD3 antibody in vitro demonstrated reduced induction of c-Jun, JunB, JunD and Fra-2. Howeve r, similar to what was observed after p38 kinase inhibition in normal mice, relative ATF-P deficiency did not prevent the development of a mononuclear cell infiltrate in the week following an inflammatory stimulus. ATF-P muta nt mice proved more susceptible to death than control mice from LPS plus D- galactosamine injection or Coxsackievirus 83 infection and had a higher inc idence of mononuclear pulmonary infiltrates after exposure to Herpes simple x virus-1. ATF-5 is essential for maximal immediate induction of adhesion m olecules and cytokine genes, but at later time points may even protect agai nst overactive immune responses.