In recent years, significant advances have been made in mechanistically understanding the role of pro- and anti-inflammatory cytokines in the regulation of immune responses against antigens, including those expressed by tumors. However, we still know very little about the regulation of pro-/anti-inflammatory genes in its natural setting, the chromatin substrate. Several mechanisms have been identified that can influence chromatin flexibility and allow dynamic changes in gene expression. Among these, chromatin modifications induced by acetylation and deacetylation of histone tails have gained wide attention. We reported previously the role of the histone deacetylase 11 (HDAC11) on the expression of IL-10, and recently we discovered the effect of HDAC6 on IL-10 production. These two deacetylases have opposite regulatory effects, and interestingly, interact through specific domains. In this proposal we plan to fully understand the role of HDAC6 and the protein complex HDAC11/HDAC6 on the production of IL-10 and other cytokines in antigen presenting cells APCs, and the consequences and relevance of this regulation to the immune response mediated by APCs. We will also study the role, cellular localization and regulatory mechanisms ruled by the interaction of HDAC11/HDAC6, and the consequences of the abrogation of this protein complex. This project will generate important knowledge about the epigenetic control of IL-10 and other cytokines mediated by HDACs. This information will help contribute to a better understanding of the mechanistic action of HDAC inhibitors over the control of immune responses mediated by APCs.
The initiation, magnitude, and duration of an immune response against antigens are tightly regulated processes involving a dynamic, orchestrated balance of pro- and anti-inflammatory pathways in immune cells. Such a delicate balance is critical for allowing efficient immune response against foreign antigens while preventing autoimmune attack against self-antigens. Recently, significant effort has been devoted to mechanistically understanding regulation of pro-/anti-inflammatory genes in its natural setting, the chromatin substrate. This knowledge will help contribute to the development of new drugs and therapies in a more tailored fashion, preventing the undesired activation/blockage of """"""""other"""""""" immune pathways. In this project we will study the influence of histone deacetylases (HDACs) on the control of the anti-inflammatory cytokine IL- 10, and how epigenetic regulation of this gene influences the immune response mediated by Antigen Presenting Cells (APCs).
|Lienlaf, M; Perez-Villarroel, P; Knox, T et al. (2016) Essential role of HDAC6 in the regulation of PD-L1 inÂ melanoma. Mol Oncol 10:735-50|
|Cheng, Fengdong; Lienlaf, Maritza; Perez-Villarroel, Patricio et al. (2014) Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells. Mol Immunol 60:44-53|
|Gonzalez-ZuÃ±iga, Marcelo; Contreras, Pablo S; Estrada, Lisbell D et al. (2014) c-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer's disease. Mol Cell 56:163-73|
|Cheng, Fengdong; Lienlaf, Maritza; Wang, Hong-Wei et al. (2014) A novel role for histone deacetylase 6 in the regulation of the tolerogenic STAT3/IL-10 pathway in APCs. J Immunol 193:2850-62|
|Woods, David M; Woan, Karrune; Cheng, Fengdong et al. (2013) The antimelanoma activity of the histone deacetylase inhibitor panobinostat (LBH589) is mediated by direct tumor cytotoxicity and increased tumor immunogenicity. Melanoma Res 23:341-8|