THE IMMUNOSUPPRESSIVE FUNGAL METABOLITE GLIOTOXIN SPECIFICALLY INHIBITS TRANSCRIPTION FACTOR NF-KAPPA-B

Opportunistic infections, such as aspergillosis, are among the most se rious complications suffered by immunocompromised patients. Aspergillu s fumigatus and other pathogenic fungi synthesize a toxic epipolythiod ioxopiperazine metabolite called gliotoxin. Gliotoxin exhibits profoun d immunosuppressive activity in vivo. It induces apoptosis in thymocyt es, splenocytes, and mesenteric lymph node cells and can selectively d eplete bone marrow of mature lymphocytes. The molecular mechanism by w hich gliotoxin exerts these effects remains unknown. Here, we report t hat nanomolar concentrations of gliotoxin inhibited the activation of transcription factor NF-kappa B in response to a variety of stimuli in T and B cells. The effect of gliotoxin was specific because, at the s ame concentrations, the toxin did clot affect activation of the transc ription factor NF-AT or of interferon-responsive signal transducers an d activators of transcription. Likewise, the activity of the constitut ively DNA-binding transcription factors Oct-1 and cyclic AMP response element binding protein (CREB), as well as the activation of protein t yrosine kinases p56(lck) and p59(fyn) was not altered by gliotoxin. Ve ry high concentrations of gliotoxin prevented NF-kappa B DNA binding i n vitro. However, in intact cells, inhibition of NF-kappa B did not oc cur at the level of DNA binding; rather, the toxin appeared to prevent degradation oi I kappa B-alpha, NF-kappa B's inhibitory subunit. Our data raise tile possibility that the immunosuppression observed during aspergillosis results in part from gliotoxin-mediated NF-kappa B inhi bition.