Role of the Toll-like receptor 4/NF-κB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages

Objective - Previous studies demonstrated that obese adipose tissue is characterized by increased infiltration of macrophages, suggesting that they might represent an important source of inflammation. Using an in vitro coculture system composed of 3T3-L1 adipocytes and RAW264 macrophages, we previously demonstrated that saturated fatty acids (FAs) and tumor necrosis factor (TNF)-alpha derived from adipocytes and macrophages, respectively, play a major role in the coculture-induced inflammatory changes.Methods and Results - Coculture of adipocytes and macrophages resulted in the activation of nuclear factor-kappa B (NF-kappa B), a primary regulator of inflammatory responses, in both cell types. Pharmacological inhibition of NF-kappa B markedly suppressed the coculture-induced production of proinflammatory cytokines and adipocyte lipolysis. Peritoneal macrophages obtained from Toll-like receptor 4 (TLR4) mutant mice exhibited marked attenuation of TNF alpha production in response to saturated FAs. Notably, coculture of hypertrophied adipocytes and TLR4-mutant macrophages resulted in marked inhibition of proinflammatory cytokine production and adipocyte lipolysis. We also observed that endogenous FAs, which are released from adipocytes via the beta(3)-adrenergic stimulation, resulted in the activation of the TLR4/NF-kappa B pathway.Conclusion - These findings suggest that saturated FAs, which are released in large quantities from hypertrophied adipocytes via the macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for TLR4, thereby inducing the inflammatory changes in both adipocytes and macrophages through NF-kappa B activation.

目的 - 先前的研究表明，肥胖脂肪组织的特征是巨噬细胞浸润增加，这表明巨噬细胞可能是炎症的一个重要来源。我们之前利用由3T3 - L1脂肪细胞和RAW264巨噬细胞组成的体外共培养系统，证明了分别源自脂肪细胞和巨噬细胞的饱和脂肪酸（FAs）和肿瘤坏死因子（TNF）-α，在共培养诱导的炎症变化中起主要作用。 方法与结果 - 脂肪细胞和巨噬细胞的共培养导致两种细胞类型中炎症反应的主要调节因子核因子 - κB（NF - κB）的激活。NF - κB的药物抑制显著抑制了共培养诱导的促炎细胞因子产生和脂肪细胞脂解。从Toll样受体4（TLR4）突变小鼠获得的腹腔巨噬细胞对饱和脂肪酸的反应中，TNF - α的产生明显减弱。值得注意的是，肥大脂肪细胞与TLR4突变巨噬细胞的共培养显著抑制了促炎细胞因子的产生和脂肪细胞脂解。我们还观察到，通过β(3) - 肾上腺素能刺激从脂肪细胞释放的内源性脂肪酸，导致了TLR4 / NF - κB通路的激活。 结论 - 这些发现表明，通过巨噬细胞诱导的脂肪细胞脂解从肥大脂肪细胞大量释放的饱和脂肪酸，作为TLR4的天然配体，从而通过NF - κB激活诱导脂肪细胞和巨噬细胞的炎症变化。