Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages.
OBJECTIVE
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.
Lagathu
Claire
C
Inserm, U680, Paris, France.
Eustace
Brenda
B
Prot
Matthieu
M
Frantz
Dan
D
Gu
Yong
Y
Bastard
Jean-Philippe
JP
Maachi
Mustapha
M
Azoulay
Stephane
S
Briggs
Michael
M
Caron
Martine
M
Capeau
Jacqueline
J
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D039682:HIV-Associated Lipodystrophy Syndrome / Q000503:physiopathology; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
D052242:Adiponectin; D019380:Anti-HIV Agents; D018925:Chemokines; D016207:Cytokines; D017320:HIV Protease Inhibitors; D017382:Reactive Oxygen Species; D018894:Reverse Transcriptase Inhibitors