一些抗逆转录病毒药物会增加氧化应激，并改变人类脂肪细胞和巨噬细胞中趋化因子、细胞因子或脂联素的产生。

Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages.

作者信息

Lagathu Claire, Eustace Brenda, Prot Matthieu, Frantz Dan, Gu Yong, Bastard Jean-Philippe, Maachi Mustapha, Azoulay Stephane, Briggs Michael, Caron Martine, Capeau Jacqueline

机构信息

Inserm, U680, Paris, France.

出版信息

Antivir Ther. 2007;12(4):489-500.

DOI:

PMID:17668557

Abstract

OBJECTIVES

Adipose tissue from patients with HIV-related lipodystrophy presents a state of chronic inflammation. Altered expression of cytokines/adipokines and macrophage infiltration could be involved in patients' insulin resistance and lipoatrophy. We tested whether antiretrovirals affected adipokine release by human subcutaneous adipocytes and cytokine/chemokine production by human macrophages and examined whether reactive oxygen species (ROS) hyperproduction was related to the effect of antiretrovirals.

METHODS

Differentiated human adipocytes and PMA-THP-1 macrophages were treated with protease inhibitors (PIs: indinavir, nelfinavir, amprenavir, lopinavir, ritonavir and atazanavir) or nucleoside reverse transcriptase inhibitors (NRTIs: stavudine, zidovudine and abacavir) for 24-48 h without or with diphenylene iodonium (DPI), an inhibitor of oxidative stress. Lipid content was assessed by Oil Red O staining and ROS production by nitroblue tetrazolium (NBT) reduction. Cytokine/chemokines, adiponectin and leptin release was evaluated by ELISA or multiplex assays.

RESULTS

In human adipocytes, PIs and NRTIs (except amprenavir, atazanavir and abacavir) reduced lipid content, adiponectin and leptin release and increased in parallel ROS production and monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 release. The effects of PIs, but not of NRTIs, were prevented by the addition of DPI. In PMA-THP-1 macrophages, all PIs, but no NRTI, increased macrophage inflammatory protein-1 alpha and MCP-1 release. Lopinavir, nelfinavir, zidovudine and stavudine markedly increased ROS production and release of IL-1 beta and tumour necrosis factor-alpha.

CONCLUSIONS

Some PIs altered adipokine secretion and lipid content through ROS production in human subcutaneous adipocytes. Thymidine analogues altered adipocyte functions but their effect on adipokine secretion was not reverted by ROS production inhibition. Increased chemokine/cytokine production by adipocytes and macrophages could be involved in macrophage recruitment and participate in lipoatrophy and insulin resistance.

摘要

目的

感染人类免疫缺陷病毒（HIV）相关脂肪代谢障碍患者的脂肪组织呈现慢性炎症状态。细胞因子/脂肪因子表达改变及巨噬细胞浸润可能与患者的胰岛素抵抗和脂肪萎缩有关。我们检测了抗逆转录病毒药物是否会影响人皮下脂肪细胞释放脂肪因子以及人巨噬细胞产生细胞因子/趋化因子，并研究了活性氧（ROS）过量产生是否与抗逆转录病毒药物的作用相关。

方法

用蛋白酶抑制剂（PIs：茚地那韦、奈非那韦、安普那韦、洛匹那韦、利托那韦和阿扎那韦）或核苷类逆转录酶抑制剂（NRTIs：司他夫定、齐多夫定和阿巴卡韦）处理分化的人脂肪细胞和佛波酯（PMA）刺激的THP-1巨噬细胞24 - 48小时，分别在有无氧化应激抑制剂二苯基碘鎓（DPI）的情况下进行。通过油红O染色评估脂质含量，通过硝基蓝四氮唑（NBT）还原法检测ROS产生。通过酶联免疫吸附测定（ELISA）或多重检测法评估细胞因子/趋化因子、脂联素和瘦素的释放。

结果

在人脂肪细胞中，PIs和NRTIs（阿普那韦、阿扎那韦和阿巴卡韦除外）降低脂质含量、脂联素和瘦素释放，同时增加ROS产生以及单核细胞趋化蛋白（MCP）-1和白细胞介素（IL）-6释放。添加DPI可阻止PIs的作用，但不能阻止NRTIs的作用。在PMA-THP-1巨噬细胞中，所有PIs（而非NRTIs）均增加巨噬细胞炎性蛋白-1α和MCP-1释放。洛匹那韦、奈非那韦、齐多夫定和司他夫定显著增加ROS产生以及IL-1β和肿瘤坏死因子-α的释放。