Loss of Ikappa B-beta is associated with prolonged NF-kappa B activity in human glial cells.
Nuclear factor-kappaB (NF-kappaB) is an inducible transcription factor central in the regulation of expression of a wide variety of genes and synthesis of several proteins involved in the generation of the immune response and inflammatory processes. In resting cells, NF-kappaB is maintained in an inactive state through cytoplasmic retention by IkappaB inhibitors. Stimulation of cells with a wide variety of inducers results in proteolytic degradation of these IkappaB proteins, leading to activation of NF-kappaB. The present study shows that interleukin-1 (IL-1) causes persistent activation of NF-kappaB in glial cells. Stimulation with IL-1 also causes rapid but transient degradation of IkappaB-alpha and IkappaB-epsilon. However, NF-kappaB remains active even after these IkappaB isoforms have returned to control levels. In contrast, the IkappaB-beta isoform fails to reappear following its initial degradation by IL-1, coincident with sustained activation of NF-kappaB. In addition, in vivo overexpression of the various IkappaB isoforms revealed that IkappaB-beta is the only isoform that has the ability to inhibit IL-1-induced NF-kappaB-driven transcription. The findings also suggest that the inability of IkappaB-alpha and IkappaB-epsilon to modulate NF-kappaB activity is due to their modification in vivo. These findings indicate that IkappaB-beta is the key regulator of the activity of NF-kappaB in human glial cells.
Bourke
E
E
Department of Pharmacology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Foster's Avenue, Blackrock, County Dublin, Ireland.
Kennedy
E J
EJ
Moynagh
P N
PN
D001483:Base Sequence; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D011994:Recombinant Proteins