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7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV13–16 November 2005, Dublin, Ireland |
PIS AND NRTIS INCREASE OXIDATIVE STRESS AND PROINFLAMMATORY CYTOKINE AND CHEMOKINE PRODUCTION IN HUMAN AND MURINE ADIPOCYTES AND MACROPHAGES
C Lagathu1, B Eustace3, D Frantz3, Y Gu3, J-P Bastard2, M Maachi2, M Briggs3, M Caron1 and J Capeau1,2
1 INSERM U680 UPMC, Paris, France; 2 Tenon Hospital, Paris, France; 3 Biology Sector, Vertex Pharmaceuticals, Inc., Cambridge, MA, USA
Antiviral Therapy 2005; Supplement 3:L21 (abstract no. 28)
OBJECTIVES: The lipodystrophic syndrome is associated with altered circulating level and adipose tissue mRNA expression of IL-6, TNFα and adiponectin. We reported that a chronic treatment of murine 3T3-L1 adipocytes with some PIs and NRTIs altered lipid metabolism, increased apoptosis and IL-6 and TNFα production, while decreased adiponectin production. We examined here the direct effect of antiretrovirals on lipid accumulation, cytokine and adiponectin release in cultured human adipocytes. Evidence suggests that adipose tissue infiltration with macrophages and the resulting chronic inflammation might play a critical role in insulin resistance and lipodystrophy. Thus we examined the effect of antiretrovirals on cytokine and chemokine production by human and murine macrophage cell lines. Finally, increased oxidative stress has been associated with insulin resistance and increased cytokine/chemokine release in adipose tissue. Finally, to approach a possible mechanism underlying the deleterious effects of antiretrovirals, we evaluated the reactive oxygen species (ROS) production.
METHODS: In vitro differentiated human ZenBio® adipocytes, PMA-treated human THP-1 monocytes and murine Raw 264.7 macrophages were treated for 24 and 48 h, with PIs (indinavir, nelfinavir, amprenavir, lopinavir, ritonavir, atazanavir) or NRTIs (stavudine, zidovudine, abacavir) at near-Cmax concentrations. Lipid accumulation was estimated by oil red O staining, survival by MTT hydrolysis, and ROS production by NBT reduction. The release of cytokines (IL-6, TNFα), chemokines (MCP-1, MIP-1α), and adiponectin was evaluated by ELISA or multiplex assays.
RESULTS: In human adipocytes, most PIs and NRTIs reduced lipid accumulation, cell survival and adiponectin production and increased ROS production, MCP-1 and IL-6 release. In Raw macrophages, lopinavir and nelfinavir increased ROS production and IL-6 release, and decreased cell survival. All PIs and NRTIs increased MCP-1 and MIP-1α production in the macrophagic cell lines.
CONCLUSIONS: These results suggest that some PIs and NRTIs can act on adipocytes and macrophages to alter chemokine and/or cytokine production through ROS production. The altered chemokine production could be involved in macrophage recruitment to adipose tissue. The altered IL-6 production could be involved in cell loss. These results suggest a link between antiretroviral molecules and lipodystrophy through ROS, chemokine and cytokine production.
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2005-11-13
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