5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 8–11 July 2003, Le Meridien Montparnasse, Paris, France

INCREASED IL-6 AND TNF-α EXPRESSION IS RELATED TO INCREASED APOPTOSIS AND DECREASED DIFFERENTIATION IN ADIPOSE TISSUE FROM PATIENTS WITH HIV-RELATED LIPOATROPHY

Antiviral Therapy 2003; 8:L10 (abstract 9)

JP Bastard^1,2, P Cervera^1,2, V Jan^1,2, M Maachi^1,2, M Caron^1,2, C Vigouroux^1,2, H Vidal³, PM Girard¹, P Levan¹, W Rozenbaum¹ and J Capeau^1,2
1INSERM U 402 and; ²Pierre et Marie Curie University Paris VI, Paris, France; and ³INSERM U 449, Lyon 1 University, Lyon, France

OBJECTIVES/AIM: The mechanisms of peripheral lipoatrophy observed in patients under highly active antiretroviral therapy (HAART) remain poorly understood. We have previously reported markedly altered differentiation and increased TNF-α mRNA expression in abdominal subcutaneous adipose tissue (AT) from lipoatrophic patients under protease inhibitors plus nucleoside reverse transcriptase inhibitors as compared to non-HIV controls. To go further, we comparatively evaluated, in a subgroup of 10 patients and six controls, the alterations of AT morphology in relation with differentiation and cytokine expression.

METHODS: The morphological parameters were: adipocyte size, interstitial fibrosis based on sirius red staining, apoptosis based on TUNEL-positive staining and the number of vessel based on alpha smooth muscle actin staining. Differentiation was evaluated by the mRNA level of adipogenic transcription factors and cytokine expression by the mRNA level of TNF-α and IL-6.

RESULTS: The level of apoptosis was increased in patients’ as compared to controls’ AT (18.4 vs 5.6%, P=0.005). Similarly, the percentage of fibrosis and the numbers of vessels were significantly increased. These parameters were correlated together. Apoptosis was inversely correlated with the differentiation markers C/EBPα (r= –0.73, P=0.005) and SREBP-1 (r= –0.66, P=0.01). Quite similar results were obtained for fibrosis and the number of vessels. IL-6 mRNA levels were increased threefold as previously reported for TNF-α. The expression of the two cytokines was inversely correlated with the differentiation markers SREBP-1 and C/EBPα. Interestingly, their expression was positively correlated with apoptosis (r=0.694, P=0.01 and r=0.504, P=0.05, respectively).

CONCLUSIONS: We observed striking alterations in patients’ AT morphology as compared with controls: adipocytes of decreased size, increased apoptosis, increased stroma with fibrosis and vessels. Most of these alterations were related together. They were also related with altered differentiation. Moreover, IL-6 and TNF-α expression was increased in relation with altered differentiation and apoptosis. Since these two cytokines act at the level of AT through autocrine/paracrine mechanisms, these results argue for a deleterious role of AT cytokines not only in altered differentiation but also in increased apoptosis, which could be responsible for clinical lipoatrophy.

Presenting author: J Capeau

2003-07-08
9

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