S100B-induced microglial and neuronal IL-1 expression is mediated by cell type-specific transcription factors.
Both the astrocytic cytokine S100B and the pro-inflammatory interleukin-1 (IL-1) are elevated in Alzheimer's disease, and each has been implicated in Alzheimer-related neuropathology. We examined the gene-regulatory events through which S100B induces IL-1beta expression. In primary microglia, S100B activated the transcription factors Sp1 and NFkappaB, followed by an increase in IL-1beta mRNA levels. The latter was blocked by a peptide inhibitor of NFkappaB or by a double-stranded oligonucleotide containing a NFkappaB-binding site to serve as "decoy" DNA and reduce available NFkappaB. But in primary cortical neurons, decoy and siRNA experiments indicated that the IL-1beta induction by S100B was mediated by Sp1 without evidence of a role for NFkappaB. Our results suggest that the elevation of S100B and IL-1 in Alzheimer brain and consequent neurodegenerative events are mediated through cell-type specific gene-regulatory events, providing mechanistic insight into connections between glial activation and neuronal dysfunction.
Liu
Ling
L
Department of Geriatrics, University of Arkansas for Medical Sciences, 629 Jack Stephens Drive #807, Little Rock, AR 72205, USA.
Li
Yuekui
Y
Van Eldik
Linda J
LJ
Griffin
W Sue T
WS
Barger
Steven W
SW
D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000494:pharmacology*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
D007375:Interleukin-1; D016328:NF-kappa B; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579158:S100b protein, rat; D016329:Sp1 Transcription Factor; D014157:Transcription Factors