Obesity is characterized by chronic low-grade inflammation with increased adipose tissue pro-inflammatory cytokine production. Acylation stimulating protein (ASP) stimulates triglyceride synthesis and glucose transport via its receptor C5L2. Circulating ASP is increased in obesity, insulin resistance and metabolic syndrome. The present study examines the effects of normal (50 nM), high physiological (200 nM) and pathological (600 nM) levels of ASP on inflammatory changes in 3T3-L1 adipocytes and J774 macrophages and the underlying mechanisms involved. Treatment with ASP for 24h increased monocyte chemoattractant protein-1 (MCP1, 800%, P<0.001) and keratinocyte-derived chemokine (KC, >150%, P<0.01) secretion in adipocytes in a dose-dependent manner, with no effect on IL-6 or adiponectin. In macrophages, ASP had no effect on these cytokines. C5a, a ligand for C5L2 and C5aR receptors, differed from ASP. Macrophage-adipocyte coculture increased MCP-1 and adiponectin secretion, and ASP further enhanced secretion (P<0.001 and P<0.05, respectively) at doses of 50 nM and 200 nM. ASP increased Ser(468) and Ser(536) phosphorylation of p65 NFκB in a time- and concentration-dependent manner (P<0.05) as well as phosphorylation of Akt Ser(473) (p=0.02). ASP and insulin stimulations of Ser(536) p65 NFκB phosphorylation were comparable (both p<0.05) but not additive. Both inhibition of PI3kinase (with wortmannin) and NFκB (with BAY11-7085) prevented ASP stimulation of MCP-1 and KC secretion in adipocytes. These findings suggest that ASP, especially at high physiologic doses, may stimulate specific inflammatory cytokines in adipocytes through PI3kinase- and NFκB-dependant pathways, thus further promoting macrophage infiltration and local inflammation in obese adipose tissue.

中文翻译：

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脂肪细胞和巨噬细胞对酰化刺激蛋白作用的差异化趋化反应。

肥胖症的特征是慢性低度炎症，脂肪组织促炎细胞因子的产生增加。酰化刺激蛋白（ASP）通过其受体C5L2刺激甘油三酸酯合成和葡萄糖转运。肥胖，胰岛素抵抗和代谢综合征会增加循环ASP。本研究检查了正常（50 nM），高生理（200 nM）和病理（600 nM）水平的ASP对3T3-L1脂肪细胞和J774巨噬细胞炎性变化的影响以及所涉及的潜在机制。ASP治疗24h剂量依赖性增加脂肪细胞中单核细胞趋化蛋白-1（MCP1，800％，P <0.001）和角化细胞衍生的趋化因子（KC，> 150％，P <0.01）的分泌，但没有剂量依赖性。在IL-6或脂联素上。在巨噬细胞中，ASP对这些细胞因子没有影响。C5a是C5L2和C5aR受体的配体，与ASP不同。巨噬细胞-脂肪细胞共培养可在50 nM和200 nM剂量下增加MCP-1和脂联素分泌，而ASP进一步增强分泌（分别为P <0.001和P <0.05）。ASP以时间和浓度依赖性方式增加p65NFκB的Ser（468）和Ser（536）磷酸化（P <0.05），以及Akt Ser（473）的磷酸化（p = 0.02）。ASP和胰岛素刺激的Ser（536）p65NFκB磷酸化具有可比性（p <0.05），但无累加性。对PI3激酶（与渥曼青霉素）和NFκB（与BAY11-7085）的抑制均阻止ASP刺激脂肪细胞中MCP-1和KC分泌。这些发现表明，特别是在高生理剂量下，ASP可能通过PI3激酶和NFκB依赖性途径刺激脂肪细胞中的特定炎症细胞因子，