Study of Histoplasma-Induced Macrophage Apoptosis

• Main Authors: Chia-Ching Lin, 林佳慶
• Other Authors: Betty A. Wu-hsieh
• Format: Others
• Language: en_US
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/25946194977696406266

碩士 === 國立臺灣大學 === 免疫學研究所 === 94 === Histoplasma is a facultative intracellular pathogen of the macrophage. In the infected host, macrophage serves not only as a target cell and an effector cell but also as an antigen donor. Work from our laboratory has shown that macrophages undergo apoptosis after taking up viable Histoplasma yeasts. The dendritic cells take up Histoplasma antigen from dying macrophages cross-prime CD8 T cells. Thus, Histoplasma-induced macrophage apoptosis is important to the activation of CD8 T cells in an infected host. However, it remains to be clarified how the fungus-host cell interaction causes macrophage apoptosis. The focus of the present study was to delineate the molecule(s) that is involved in inducing macrophage apoptosis. First, I found that inducible nitric oxide synthase (iNOS) was upregulated in macrophages after infection by Histoplasma. However, the apoptosis rate was not reduced in iNOS-deficient macrophages nor in macrophages treated with N-acetyl-cysteine, a reactive oxygen species scavenger, demonstrating neither reactive nitrogen nor oxygen intermediates is involved in macrophage apoptosis. Interestingly, TNF-a production was high in macrophages after uptake of viable Histoplasma. To investigate whether TNF-a is involved in inducing macrophage apoptosis, macrophages from TNF-a-/-, TNFR1-/-, TNFR2-/- and TNFR1-/-R2-/- mice were used. The results showed that in macrophages deficient in TNF-a, TNFR1, TNFR2 or TNFR1R2, the rate of Histoplasma-induced apoptosis was dramatically reduced. Both caspase-8 and pan-caspase inhibitors also significantly reduced macrophage apoptosis. The results of this study demonstrated that production of TNF-a, which through the TNF receptor-transduced signals mediates Histoplasma-induced macrophage apoptosis.