Inhibition of HDAC Enzymes Contributes to Differential Expression of Pro-Inflammatory Proteins in the TLR-4 Signaling Cascade

International Journal of Molecular Sciences

Julia Häusler¹  Gerd Geisslinger¹  SayedAdham Husseini¹  Moritz Möller¹  Ulrike Weiss¹  Christine Manderscheid¹  Ellen Niederberger¹ 

[1] Pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany;

关键词: HDAC;    acetylation;    macrophages;    inflammation;   

DOI  :  10.3390/ijms21238943

来源: DOAJ

【 摘 要 】

Class I and II histone deacetylases (HDAC) are considered important regulators of immunity and inflammation. Modulation of HDAC expression and activity is associated with altered inflammatory responses but reports are controversial and the specific impact of single HDACs is not clear. We examined class I and II HDACs in TLR-4 signaling pathways in murine macrophages with a focus on IκB kinase epsilon (IKKε) which has not been investigated in this context before. Therefore, we applied the pan-HDAC inhibitors (HDACi) trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) as well as HDAC-specific siRNA. Administration of HDACi reduced HDAC activity and decreased expression of IKKε although its acetylation was increased. Other pro-inflammatory genes (IL-1β, iNOS, TNFα) also decreased while COX-2 expression increased. HDAC 2, 3 and 4, respectively, might be involved in IKKε and iNOS downregulation with potential participation of NF-κB transcription factor inhibition. Suppression of HDAC 1–3, activation of NF-κB and RNA stabilization mechanisms might contribute to increased COX-2 expression. In conclusion, our results indicate that TSA and SAHA exert a number of histone- and HDAC-independent functions. Furthermore, the data show that different HDAC enzymes fulfill different functions in macrophages and might lead to both pro- and anti-inflammatory effects which have to be considered in therapeutic approaches.

【 授权许可】

Unknown