抗凋亡蛋白c-FLIP促進LPS誘發巨噬細胞發炎反應

c-FLIP Enhances LPS-induced Inflammation in Macrophages

死亡接受器誘發細胞凋亡過程中，c-FLIP 扮演抑制細胞凋亡的角色。在一些慢性發炎疾病的病灶處，有巨噬細胞浸潤的現象，且這些巨噬細胞有大量c-FLIP的表現，造成巨噬細胞抗拒細胞凋亡訊息，而加強發炎現象。本研究以老鼠巨噬細胞，Raw 264.7，作為材料，探討c-FLIPL 對巨噬細胞活化之影響。結果發現以LPS 刺激穩定表現c-FLIPL 蛋白質的Raw 264.7 細胞（Raw 264.7/c-FLIPL），會明顯增加促發炎反應細胞激素TNFα mRNA 的表現及TNFα 分泌，進一步分析發現造成TNFα 增加的原因，是穩定表現c-FLIPL 會使MyD88 表現增加，進而增加p38的磷酸化，最終造成了TNFα 分泌量增多，顯示c-FLIPL 參與巨噬細胞引起的發炎反應。本研究證實c-FLIPL 過度表現會促進發炎反應，因此在開發治療及預防發炎疾病的藥物或保健食品可以考慮將c-FLIPL 做為藥物的標靶因子。

Cellular FLICE-inhibitory protein (c-FLIP) is a well-established inhibitor ofdeath receptor-initiated apoptosis. Chronic inflammatory disease is characterized bymacrophages infiltrate in the lesion location. The expression of c-FLIP in infiltratemacrophages and its correlation to accumulation of inflammatory cells in lesion tissuesuggests that c-FLIP potentially extends the lifespan of macrophages and thuscontributes to the progression of inflammation. In this study we attempt to verify thec-FLIPL effect on transmitting activated signals upon LPS stimulation in macrophage.We found that c-FLIPL-expressing macrophage, Raw 264.7/c-FLIPL, could increaseTNFα mRNA expression and TNFα secretion. The mechanism of enhancing secretionof TNFα was through the enhancement of adaptor protein, MyD88, then increasedp38 phosphorylation under LPS stimulation. It is obviously c-FLIPL may transduceLPS-stimulated signal in macrophages. The results suggest that c-FLIPL could act as avalid pharmaceutical target for the treatment and prevention of chronic inflammatorydiseases in health food or drug development.