743-W.
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The Regulation of Neurotrophic Factor Activities Following HIV-1 Infection and Immune Activation of Mononuclear Phagocytes
A. L. Lopez, R. L. Cotter, D. A. Erichsen, H. Peng, L. Gendelman, A. Shibata, H. E. Gendelman, and J. Zheng*
Univ. of Nebraska Med. Ctr., Omaha
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Background: Mononuclear phagocyte (MP, brain macrophage and microglia) activation and neuronal injury are major features of HIV-1 encephalitis (HIVE), the histopathological correlate for HIV-1-associated dementia (HAD). MP activation seems to play a significant role in disease causation and propagation. MP activation may be initiated by neuronal injury through the production of neuronal chemokines, such as fractalkine. Fractalkine may act to recruit and activate MP to initiate neuronal repair. However, the presence of activated MP may also perpetuate inflammation. In order to assess this paradoxical role of MP in HAD pathogenesis, we determined changes in the levels of neurotrophic factors and cytokines produced by human monocyte-derived macrophages (MDM) following immune activation and/or viral infection.
Methods: RT-PCR and ELISA were used to determine the mRNA and secreted protein levels of brain-derived neurotrophic factor (BDNF), basic fibroblast growth factor (bFGF), beta neuronal growth factor (beta-NGF), and transforming growth factor-1 beta (TGF-1beta). Quantitative determinations of neuronal differentiation and viability were performed using neuronal antigen and DNA fragmentation ELISAs.
Results: MDM constitutively produced the neurotrophins BDNF, bFGF, beta-NGF and TGF-1beta. Fractalkine minimally altered the production of these neurotrophins, while HIV-1 infection of MDM significantly diminished the production of beta-NGF and TGF-1beta. This finding corresponded with neuronal damage. Interestingly, bFGF was not significantly altered by viral infection. However, tumor necrosis factor alpha (TNF-alpha) and macrophage inflammatory protein-1 alpha (MIP-1alpha) were shown to be increased. The levels of BDNF, bFGF, beta-NGF, TGF-1beta, and MIP-1alpha observed in MDM-conditioned media did not elicit neuronal apoptosis. In contrast, TGF-1beta, BDNF and beta-NGF all protected against glutamate (50 mM) induced neuronal death.
Conclusions: These results demonstrate that MP neurotrophic factor secretions are altered by viral infection and immune activation. These changes may play an important role in the progression of HAD.
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