The generation of semi-mature dendritic cells by inhibiting acetyl-CoA carboxylases

Semi-mature DCs;CP-640186;Acetyl-CoA carboxylase;Lipid metabolism.;610

NGUYENPHUONGTHUY의과대학 의과학과 ;

University:서울대학교 대학원

关键词: Semi-mature DCs;    CP-640186;    Acetyl-CoA carboxylase;    Lipid metabolism.;    610;   

Others  :  http://s-space.snu.ac.kr/bitstream/10371/133006/1/000000066638.pdf

美国|英语

来源: Seoul National University Open Repository

【 摘 要 】

Introduction: The adoptive transfer of tolerogenic dendritic cells has been employed as a promising tool for transplantation as well as treatment of autoimmune diseases. Some different tolerogenic dendritic cells share the feature of semi-mature state. Also current studies have demonstrated that fatty-acid synthesis is important for dendritic cell activation while fatty-acid oxidation is necessary for maintaining immature state. Therefore, in this study, I focused on blocking acetyl-coA carboxylases which can inhibit fatty-acid synthesis and promote fatty-acid oxidation to generate the semi-mature dendritic cells which may have potential for immunotherapy.Methods: Bone marrow cells (BMs) were isolated from 8-week-old C57BL/6 female mice then have been cultured for 8 days (in RPMI complete media with 10 ng/ml GM-CSF and 1.5 ng/ml IL-4) to differentiate to dendritic cells (DCs). At day 8, bone marrow-derived dendritic cells (BMDCs) were pre-incubated for 30 minutes with CP-640186 (CP), an acetyl-CoA carboxylase (ACC) inhibitor, following by LPS treatment up to 24hours for maturation. BMDCs and BMDCs with LPS treatment only were used as control groups. The effect of CP on BMDC maturation was investigated through DCs phenotypic and functional studies.Results: The effect of CP to block ACCs in DCs was confirmed. Next, the expression of MHC class II and co-stimulatory molecules (CD80, CD86 and CD40) on LPS-treated BMDCs were down-regulated by CP with concentration dependent manner. Consistently, the secretion of pro-inflammatory cytokines (IL-6, IFN-γ, IL-12p70) also decreased. Interestingly, the chemokine receptor, CCR5 was up-regulated while the homing receptor, CCR7 was down-regulated in CP treatment groups. Moreover, these groups also increased antigen uptake capacity. Finally, in the presence of CP, LPS-treated BMDCs failed to activate antigen-specific CD4+T cells proliferation. Conclusions: In summary, our data elucidates that DCs with semi-mature phenotype and characteristic of immature-like cells were generated by ACCs inhibition. This study has implication for the development of metabolism based-approaches in DC-mediated immunotherapies.