S100B/RAGE-dependent activation of microglia via NF-kappaB and AP-1 Co-regulation of COX-2 expression by S100B, IL-1beta and TNF-alpha.
Extracellular S100B is known to affect astrocytic, neuronal and microglial activities, with different effects depending on its concentration. Whereas at relatively low concentrations S100B exerts trophic effects on neurons and astrocytes, at relatively high concentrations the protein causes neuronal apoptosis and activates astrocytes and microglia, thus potentially representing an endogenous factor implicated in neuroinflammation. We have reported that RAGE ligation by S100B in BV-2 microglia results in the upregulation of expression of the pro-inflammatory cyclo-oxygenase 2 (COX-2) via parallel Ras-Cdc42-Rac1-dependent activation of c-Jun NH(2) terminal protein kinase (JNK) and Ras-Rac1-dependent stimulation of NF-kappaB transcriptional activity. We show here that: (1) S100B also stimulates AP-1 transcriptional activity in microglia via RAGE-dependent activation of JNK; (2) S100B upregulates IL-1beta and TNF-alpha expression in microglia via RAGE engagement; and (3) S100B/RAGE-induced upregulation of COX-2, IL-1beta and TNF-alpha expression requires the concurrent activation of NF-kappaB and AP-1. We also show that S100B synergizes with IL-1beta and TNF-alpha to upregulate on COX-2 expression in microglia. Given the crucial roles of COX-2, IL-1beta and TNF-alpha in the inflammatory response, we propose that, by engaging RAGE, S100B might play an important role in microglia activation in the course of brain damage.
Bianchi
Roberta
R
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, C.P. 81 Succ. 3, 06122 Perugia, Italy.
Giambanco
Ileana
I
Donato
Rosario
R
D000818:Animals; D002417:Cattle; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004660:Encephalitis / Q000378:metabolism* / Q000503:physiopathology; D005911:Gliosis / Q000378:metabolism* / Q000503:physiopathology; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D053583:Interleukin-1beta; D016328:NF-kappa B; D009414:Nerve Growth Factors; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579159:S100b protein, mouse; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2