CONSTITUTIVE NF-KAPPA-B ACTIVITY IN NEURONS

NF-kappa B is an inducible transcription factor present in many cell t ypes in a latent cytoplasmic form. So far, only immune cells including mature B cells, thymocytes, and adherent macrophages have been report ed to contain constitutively active forms of NF-kappa B in the nucleus . A recent study showed that the human immunodeficiency virus type 1 ( HIV-1) promoter is highly active in several brain regions of transgeni c mice (J. R. Corboy, J. M. Buzy, M. C. Zink, and J. E. Clements, Scie nce 258:1804-1807, 1992). Since the activity of this viral enhancer is governed mainly by two binding sites for NF-kappa B, we were prompted to investigate the state of NP-kappa B activity in neurons. Primary n euronal cultures derived from rat hippocampus and cerebral cortex show ed a high constitutive expression of an HIV-1 long terminal repeat-dri ven luciferase reporter gene, which was primarily dependent on intact NF-kappa B binding sites and was abolished upon coexpression of the NF -kappa B-specific inhibitor I kappa B-alpha. Indirect immunofluorescen ce and confocal laser microscopy showed that the activity of NF-kappa B correlated with the presence of the NF-kappa B subunits p50 and RelA (p65) in nuclei of cultured neurons. NF-kappa B was also constitutive ly active in neurons in vivo. As investigated by electrophoretic mobil ity shift assays, constitutive NF-kappa B DNA-binding activity was hig hly enriched in fractions containing neuronal nuclei prepared from rat cerebral cortex. Nuclear NF-kappa B-specific immunostaining was also seen in cryosections from mouse cerebral cortex and hippocampus. Only a subset of neurons was stained. Activated NF-kappa KB in the brain is likely to participate in normal brain function and to reflect a disti nct state of neuronal activity or differentiation. Furthermore, it may explain the high level of activity of the HIV-1 enhancer in neurons, an observation potentially relevant for the etiology of the AIDS demen tia complex caused by HIV infection of the central nervous system.