C/EBPβ regulates multiple IL-1β-induced human astrocyte inflammatory genes

Background: ccaat enhancer-binding protein (c/ebp)β regulates gene expression in multiple organ systems and cell types,including astrocytes in the central nervous system (cns). inflammatory stimuli,interleukin (il)-1β,tumor necrosis factor-α,human immunodeficiency virus (hiv)-1 and lipopolysaccharide induce astrocyte c/ebpβ expression. c/ebpβ is detectable in brains of alzheimer's disease (ad),parkinson's disease (pd) and hiv-1-associated dementia (had) patients,yet little is known about how c/ebpβ contributes to astrocyte gene regulation during neuroinflammation.methods: the expression of 92 human inflammation genes was compared between il-1β-treated primary human astrocytes and astrocytes transfected with c/ebpβ-specific small interfering (si)rna prior to il-1β treatment for 12 h. transcripts altered by > two-fold compared to control were subjected to one-way analysis of variance and newman-keuls post-test for multiple comparisons. expression of two genes,cyclooxygenase-2 (cox-2) and bradykinin receptor b2 (bdkrb2) was further confirmed in additional human astrocyte donors. astrocytes were treated with mitogen-activated protein kinase-selective inhibitors,then with il-1β for 12 or 24 h followed by cox-2 and bdkrb2,expression analyses.results: il-1β altered expression of 29 of 92 human inflammation genes by at least two-fold in primary human astrocytes in 12 h. c/ebpβ knockdown affected expression of 17 out of 29 il-1β-regulated genes by > 25%. two genes relevant to neuroinflammation,cox-2 and bdkrb2,were robustly decreased and increased,respectively,in response to c/ebpβ knockdown,and expression was confirmed in two additional donors. cox-2 and bdkrb2 mrna remained altered in sirna-transfected astrocytes at 12,24 or 72 h. inhibiting p38 kinase (p38k) activation blocked il-1β-induced astrocyte cox-2 mrna and protein expression,but not il-1β-induced astrocyte bdkrb2 expression. inhibiting extracellular-regulated kinase (erk)1/2 activation blocked il-1β-induced bdkrb2 mrna expression while increasing cox-2 expression.conclusion: these data support an essential role for il-1β in the cns and identify new c/ebpβ functions in astrocytes. additionally,this work suggests p38k and erk1/2 pathways may regulate gene expression in a complementary manner to fine tune the il-1β-mediated astrocyte inflammatory response. delineating a role for c/ebpβ and other involved transcription factors in human astrocyte inflammatory response may lead to effective therapies for ad,pd,had and other neurological disorders. © 2012 fields and ghorpade licensee biomed central ltd.