アクティブボード・２０１４年１１月
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研究発表を行った学会；
・第７６回　日本血液学会学術集会
　２０１４年１０月３１日〜１１月　２日（大阪）
タイトル；TAK1, macropinocytosis mediate anti- to pro-inflammatory macrophage differentiation by Nef.
発表者；橋本　倫拓　氏
　　　（熊本大学　エイズ学研究センター　鈴　研究室）
Abstract；
Functionally, macrophages are classified into two types, anti-inflammatory M2 and pro-inflammatory M1. We recently revealed that soluble HIV-1 proteins, particularly the pathogenetic protein Nef, preferentially activate M2-macrophages and drive them towards an M1-like macrophages (J Immunol 2012), which might explain the sustained immune activation seen in HIV-1-infected patients. In this study, we found that the preferential effect of Nef on M2-macrophages was mediated by TAK1 and macropinocytosis (Cell Death Dis, in press). As with MAP kinases and NF-kB pathway, Nef markedly activated TAK1, in M-CSF-derived M2 but not in GM-CSF-derived M1-macrophages. Indeed, the TAK1 inhibitor 5Z-7-oxozeaenol as well as the ectopic expression of a dominant-negative mutant of TAK1 or TRAF2, an upstream molecule of TAK1, inhibited Nef-induced signaling activation and M1-like phenotypic differentiation of M2-macrophages. Meanwhile, the preferential effect of Nef on M2-macrophages correlated with the fact the Nef entered M2-macrophages more efficiently than M1-macrophages. Importantly, the macropinosome formation inhibitor EIPA completely blocked the internalization of Nef into M2-macrophages. Because the macropinocytosis activity of M2-macrophages was higher than that of M1-macrophages, our findings indicate that Nef enters M2-macrophages efficiently by exploiting their higher macropinocytosis activity and drives them towards M1-like macrophages by activating TAK1.