炎症受体CD40在人类脂肪细胞上表达：对淋巴细胞与脂肪细胞间相互作用的作用。

The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes.

作者信息

Poggi M, Jager J, Paulmyer-Lacroix O, Peiretti F, Gremeaux T, Verdier M, Grino M, Stepanian A, Msika S, Burcelin R, de Prost D, Tanti J F, Alessi M C

机构信息

Faculté de Médecine, Inserm U626, Marseille Cedex 5, France.

出版信息

Diabetologia. 2009 Jun;52(6):1152-63. doi: 10.1007/s00125-009-1267-1. Epub 2009 Jan 31.

DOI:10.1007/s00125-009-1267-1

PMID:19183933

Abstract

AIMS/HYPOTHESIS: Obesity is associated with adipose tissue inflammation. The CD40 molecule, TNF receptor superfamily member 5 (CD40)/CD40 ligand (CD40L) pathway plays a role in the onset and maintenance of the inflammatory reaction, but has not been studied in human adipose tissue. Our aim was to examine CD40 expression by human adipocytes and its participation in adipose tissue inflammation.

METHODS

CD40 expression was investigated in human whole adipose tissue and during adipocyte differentiation by real-time PCR, Western blot and immunohistochemistry. The CD40/CD40L pathway was studied using recombinant CD40L (rCD40L) in adipocyte culture and neutralising antibodies in lymphocyte/adipocyte co-culture.

RESULTS

CD40 mRNA levels in subcutaneous adipose tissue were higher in the adipocyte than in the stromal-vascular fraction. CD40 expression was upregulated during adipocyte differentiation. Addition of rCD40L to adipocytes induced mitogen activated protein kinase (MAPK) activation, stimulated inflammatory adipocytokine production, and decreased insulin-induced glucose transport in parallel with a downregulation of IRS1 and GLUT4 (also known as SCL2A4). rCD40L decreased the expression of lipogenic genes and increased lipolysis. CD40 mRNA levels were significantly higher in subcutaneous adipose tissue than in visceral adipose tissue of obese patients and were positively correlated with BMI, and with IL6 and leptin mRNA levels. Lymphocyte/adipocyte co-culture led to an upregulation of proinflammatory adipocytokines and a downregulation of leptin and adiponectin. Physical separation of the two cell types attenuated these effects, suggesting the involvement of a cell-cell contact. Blocking the CD40/CD40L interaction with neutralising antibodies reduced IL-6 secretion from adipocytes.

CONCLUSIONS/INTERPRETATION: Adipocyte CD40 may contribute to obesity-related inflammation and insulin resistance. T lymphocytes regulate adipocytokine production through both the release of soluble factor(s) and heterotypic contact with adipocytes involving CD40.

摘要

目的/假设：肥胖与脂肪组织炎症相关。CD40分子，即肿瘤坏死因子受体超家族成员5（CD40）/CD40配体（CD40L）通路在炎症反应的发生和维持中起作用，但尚未在人体脂肪组织中进行研究。我们的目的是检测人脂肪细胞中CD40的表达及其在脂肪组织炎症中的作用。

方法

通过实时聚合酶链反应、蛋白质印迹法和免疫组织化学法研究人全脂肪组织及脂肪细胞分化过程中CD40的表达。在脂肪细胞培养中使用重组CD40L（rCD40L）并在淋巴细胞/脂肪细胞共培养中使用中和抗体来研究CD40/CD40L通路。

结果

皮下脂肪组织中脂肪细胞的CD40信使核糖核酸水平高于基质血管部分。脂肪细胞分化过程中CD40表达上调。向脂肪细胞中添加rCD40L可诱导丝裂原活化蛋白激酶（MAPK）激活，刺激炎症性脂肪细胞因子产生，并降低胰岛素诱导的葡萄糖转运，同时IRS1和葡萄糖转运蛋白4（也称为SCL2A4）表达下调。rCD40L降低了生脂基因的表达并增加了脂肪分解。肥胖患者皮下脂肪组织中的CD40信使核糖核酸水平显著高于内脏脂肪组织，且与体重指数、白细胞介素6和瘦素信使核糖核酸水平呈正相关。淋巴细胞/脂肪细胞共培养导致促炎脂肪细胞因子上调以及瘦素和脂联素下调。两种细胞类型的物理分离减弱了这些作用，提示细胞间接触参与其中。用中和抗体阻断CD40/CD40L相互作用可减少脂肪细胞分泌白细胞介素6。

结论/解读：脂肪细胞CD40可能导致肥胖相关炎症和胰岛素抵抗。T淋巴细胞通过释放可溶性因子以及与涉及CD40的脂肪细胞异型接触来调节脂肪细胞因子的产生。