Shanmugam Narkunarajaa, Figarola James L, Li Yan, Swiderski Piotr M, Rahbar Samual, Natarajan Rama
Department of Diabetes, Beckman Research Institute of the City of Hope, 1500 East Duarte Rd., Duarte, CA 91010, USA.
Diabetes. 2008 Apr;57(4):879-88. doi: 10.2337/db07-1204. Epub 2007 Nov 14.
The reactions of carbohydrate- or lipid-derived intermediates with proteins lead to the formation of Maillard reaction products, which subsequently leads to the formation of advanced glycation/lipoxidation end products (AGE/ALEs). Levels of AGE/ALEs are increased in diseases like diabetes. Unlike AGEs, very little is known about ALE effects in vitro. We hypothesized that ALEs can have proinflammatory effects in monocytes.
In a profiling approach, conditioned media from THP-1 cells either cultured in normal glucose (5.5 mmol/l) or treated with MDA-Lys or MDA alone were hybridized to arrays containing antibodies to 120 known human cytokines/chemokines. Pathway analyses with bioinformatics software were used to identify signalling networks.
Synthetic ALE (malondialdehyde-lysine [MDA-Lys]) (50 micromol/l) could induce oxidant stress and also activate the transcriptional factor nuclear factor-kappaB (NF-kappaB) in THP-1 monocytes. MDA-Lys also significantly increased the expression of key candidate proinflammatory genes, interferon-gamma-inducible protein-10, beta1- and beta2-integrins, cyclooxygenase-2 (COX-2), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 and -8, and inducible nitric-oxide synthase, which are also associated with monocyte dysfunction. Several key target proinflammatory proteins were significantly induced by MDA-Lys relative to normal glucose or MDA alone, including MCP-1; tumor necrosis factor ligand superfamily member-14; chemokine CC motif ligand-11 (CCL11); growth-related oncogene-alpha, -beta, and -gamma; and chemokine CXC motif ligand-13. Bioinformatics analyses identified a network of chemokine signaling among MDA-Lys-regulated genes. MDA-Lys also increased monocyte binding to vascular smooth muscle and endothelial cells. Furthermore, plasma from diabetic rats showed significantly higher levels of MDA-Lys and CCL11.
These new results suggest that ALEs can promote monocyte activation and vascular complications via induction of inflammatory pathways and networks.
碳水化合物或脂质衍生中间体与蛋白质的反应会导致美拉德反应产物的形成，进而导致晚期糖基化/脂氧化终产物（AGE/ALE）的形成。在糖尿病等疾病中，AGE/ALE的水平会升高。与AGE不同，关于ALE在体外的作用知之甚少。我们假设ALE在单核细胞中具有促炎作用。
采用分析方法，将在正常葡萄糖（5.5 mmol/l）中培养或用丙二醛-赖氨酸（MDA-Lys）或单独用丙二醛（MDA）处理的THP-1细胞的条件培养基与含有针对120种已知人类细胞因子/趋化因子的抗体的阵列进行杂交。使用生物信息学软件进行通路分析以识别信号网络。
合成的ALE（丙二醛-赖氨酸[MDA-Lys]）（50 μmol/l）可诱导氧化应激，并激活THP-1单核细胞中的转录因子核因子-κB（NF-κB）。MDA-Lys还显著增加了关键候选促炎基因、干扰素-γ诱导蛋白-10、β1和β2整合素、环氧合酶-2（COX-2）、单核细胞趋化蛋白-1（MCP-1）、白细胞介素-6和-8以及诱导型一氧化氮合酶的表达，这些也与单核细胞功能障碍有关。相对于正常葡萄糖或单独的MDA，MDA-Lys显著诱导了几种关键的靶促炎蛋白，包括MCP-1；肿瘤坏死因子配体超家族成员-14；趋化因子CC基序配体-11（CCL11）；生长相关癌基因-α、-β和-γ；以及趋化因子CXC基序配体-13。生物信息学分析确定了MDA-Lys调节基因之间的趋化因子信号网络。MDA-Lys还增加了单核细胞与血管平滑肌和内皮细胞的结合。此外，糖尿病大鼠的血浆中MDA-Lys和CCL11水平显著更高。
这些新结果表明，ALE可通过诱导炎症途径和网络促进单核细胞活化和血管并发症。
