Anti-inflammatory effect of Trichostatin-A on murine bone marrow-derived macrophages.
Histone deacetylase (HDAC) inhibitors were recently shown to suppress inflammatory responses in models of autoimmune and inflammatory diseases. In this study, the anti-inflammatory effects of five different HDAC inhibitors on lipopolysaccharide-(LPS)-stimulated macrophages were compared and the mechanisms of these effects were demonstrated. Trichostatin-A (TSA) and scriptaid, two of the five HDAC inhibitors, showed the most potent inhibitory effects on the nitric-oxide (NO) production of RAW264.7 cells and bone-marrow-derived macrophages (BMDMs). TSA significantly decreased the mRNA and protein levels of the proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1beta, whereas the pretreatment with TSA increased the level of the immunosuppressive cytokine IL-10. TSA also reduced the cell surface markers of the maturity of the macrophages. Furthermore, a longer duration (up to 8 h) of hyperacetylation was observed in the cells that had been exposed to TSA, whereas the hyperacetylation induced by the other HDAC inhibitors was absent after 8 h. These results demonstrated that TSA is the most potent HDAC inhibitor of histone deacetylation and has the greatest ability to induce anti-inflammatory activity in cloned and naïve macrophages. These results are expected to serve as a guide for future studies on the ability of HDAC inhibitors to inhibit acute and chronic inflammatory diseases.
Han
Sang-Bae
SB
College of Pharmacy, Chungbuk National University, Cheongju, 361-763, Korea.
Lee
Jae Kwon
JK
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D006898:Hydroxylamines / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D006898:Hydroxylamines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011804:Quinolines; D012333:RNA, Messenger; C410733:scriptaid; D009569:Nitric Oxide; C012589:trichostatin A; D006655:Histone Deacetylases