Histone deacetylase (HDAC) inhibitors reduce the glial inflammatory response in vitro and in vivo
| Autor: | Flavio Moroni, Giuseppe Faraco, Alberto Chiarugi, Gianluca Fossati, Silvia Fossati, Paolo Mascagni, Marco Porcu, Maria Pittelli, Leonardo Cavone |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Cell Survival Histone Deacetylases lcsh:RC321-571 Mice medicine Animals Epigenetics lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Transcription factor Cells Cultured Inflammation c-FOS Histone deacetylase 5 biology Microglia HDAC11 SOCS Histone Deacetylase Inhibitors Mice Inbred C57BL AP-1 transcription factor Histone medicine.anatomical_structure Animals Newborn Neurology biology.protein Cancer research microRNA-146 Histone deacetylase Inflammation Mediators Neuroglia Transcription NFκB |
| Zdroj: | Neurobiology of Disease, Vol 36, Iss 2, Pp 269-279 (2009) |
| ISSN: | 0969-9961 |
| Popis: | Histone deacetylase inhibitors (HDACi) are emerging tools for epigenetic modulation of gene expression and suppress the inflammatory response in models of systemic immune activation. Yet, their effects within the brain are still controversial. Also, whether HDACs are expressed in astrocytes or microglia is unclear. Here, we report the identification of transcripts for HDAC 1-11 in cultured mouse glial cells. Two HDACi such as SAHA and ITF2357 induce dramatic increase of histone acetylation without causing cytotoxicity of cultured cells. Of note, the two compounds inhibit expression of pro-inflammatory mediators by LPS-challenged glial cultures, and potentiate immunosuppression triggered by dexamethasone in vitro. The anti-inflammatory effect is not due to HDACi-induced transcription of immunosuppressant proteins, (including SOCS-1/3) or microRNA-146. Rather, it is accompanied by direct alteration of transcription factor DNA binding and ensuing transcriptional activation. Indeed, both HDACi impair NFkappaB-dependent IkappaBalpha resynthesis in glial cells exposed to LPS, and, among various AP1 subunits and NFkappaB p65, affect the DNA binding activity of c-FOS, c-JUN and FRA2. Importantly, ITF2357 reduces the expression of pro-inflammatory mediators in the striatum of mice iontophoretically injected with LPS. Data demonstrate that mouse glial cells have ongoing HDAC activity, and its inhibition suppresses the neuroinflammatory response because of a direct impairment of the transcriptional machinery. |
| Databáze: | OpenAIRE |
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