Department of Microbiology and Immunology, Temple University School of Medicine, 3500 North Broad Street, Philadelphia, Pennsylvania 19140, USA.
Lipids Health Dis. 2010 Feb 1;9:12. doi: 10.1186/1476-511X-9-12.
Acute and chronic inflammation play essential roles in inflammatory/autoimmune conditions. Protective anti-inflammatory effects of the n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were reported in animal models of colitis, sepsis, and stroke. Since dendritic cells (DC) represent the essential cellular link between innate and adaptive immunity and have a prominent role in tolerance for self-antigens, we sought to investigate the impact of DHA on DC maturation and proinflammatory cytokine production.
Murine bone marrow-derived DC were treated with DHA and stimulated with various toll-like receptor (TLR) ligands. Flow cytometry was used to determine the levels of surface maturation markers and endocytic activity. Cytokine expression and secretion were measured by real-time RT-PCR and ELISA assays. PPARgamma and NFkappaB activity in nuclear extracts were determined by binding to specific oligonucleotide sequences using ELISA-based assays. In vivo effects of DHA were assessed in splenic DC from LPS-inoculated mice maintained on a DHA-enriched diet.
DHA maintained the immature phenotype in bone marrow-derived DC by preventing the upregulation of MHCII and costimulatory molecules (CD40, CD80 and CD86) and maintaining high levels of endocytic activity. DHA inhibited the production of pro-inflammatory cytokines, including the IL-12 cytokine family (IL-12p70, IL-23, and IL-27), from DC stimulated with TLR2, 3, 4, and 9 ligands. DHA inhibition of IL-12 expression was mediated through activation of PPARgamma and inhibition of NFkappaBp65 nuclear translocation. DHA exerted a similar inhibitory effect on IL-12 and IL-23 expression in vivo in LPS-inoculated mice maintained on a DHA-enriched diet.
Exposure of bone marrow-derived DC to DHA resulted in the maintenance of an immature phenotype and drastic reduction in proinflammatory cytokine release. DHA inhibited the expression and secretion of the IL-12 cytokine family members (IL-12p70, IL-23 and IL-27), which play essential roles in the differentiation of the proinflammatory Th1/Th17 effector cells. The effect of DHA on IL-12 expression was mediated through activation of PPARgamma and inhibition of NFkappaB. Inhibition of IL-12 and IL-23 expression was also evident in splenic DC from mice fed a DHA-enriched diet, suggesting that dietary DHA acts as an anti-inflammatory agent in vivo.
急性和慢性炎症在炎症/自身免疫性疾病中起着至关重要的作用。n-3 脂肪酸二十二碳六烯酸（DHA）和二十碳五烯酸（EPA）在结肠炎、败血症和中风的动物模型中具有保护抗炎作用。由于树突状细胞（DC）代表先天免疫和适应性免疫之间的基本细胞联系，并且在自身抗原的耐受中起重要作用，因此我们试图研究 DHA 对 DC 成熟和促炎细胞因子产生的影响。
用 DHA 处理骨髓来源的 DC，并与各种 Toll 样受体（TLR）配体刺激。流式细胞术用于确定表面成熟标志物和内吞作用的水平。通过实时 RT-PCR 和 ELISA 测定细胞因子表达和分泌。通过 ELISA 测定核提取物中 PPARγ 和 NFkappaB 活性与特定寡核苷酸序列的结合。通过用富含 DHA 的饮食维持 LPS 接种小鼠的脾脏 DC 来评估 DHA 的体内作用。
DHA 通过防止 MHCII 和共刺激分子（CD40、CD80 和 CD86）的上调并保持高水平的内吞作用，维持骨髓来源的 DC 的未成熟表型。DHA 抑制 TLR2、3、4 和 9 配体刺激的 DC 产生促炎细胞因子，包括 IL-12 细胞因子家族（IL-12p70、IL-23 和 IL-27）。DHA 通过激活 PPARγ 和抑制 NFkappaBp65 核易位来抑制 IL-12 表达。DHA 在富含 DHA 的饮食维持的 LPS 接种小鼠体内也对 IL-12 和 IL-23 表达具有相似的抑制作用。
暴露于 DHA 的骨髓来源的 DC 导致维持未成熟表型和促炎细胞因子释放的急剧减少。DHA 抑制 IL-12 细胞因子家族成员（IL-12p70、IL-23 和 IL-27）的表达和分泌，这些细胞因子在促炎 Th1/Th17 效应细胞的分化中起关键作用。DHA 对 IL-12 表达的影响是通过激活 PPARγ 和抑制 NFkappaB 介导的。富含 DHA 的饮食喂养的小鼠脾脏 DC 中也可见 IL-12 和 IL-23 表达的抑制，表明膳食 DHA 在体内作为抗炎剂发挥作用。
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