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標題: 在 Ramos B 細胞株中類鐸受體 7 接合子誘發細胞自噬及其對 B 細胞抗原接受器造成之細胞凋亡影響之研究
Toll-like Receptor 7 Ligands Induce Autophagy and Their Effects on B cell Antigen Receptor Mediated Apoptosis in Ramos B cells
作者: 樂以梅
Yueh, Yi-Mei
關鍵字: autophagy
Toll-like receptor (TLR)
B cell antigen receptor (BCR)
B 細胞抗原接受器
出版社: 生物醫學研究所
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摘要: 細胞自噬 ( autophagy ) 在所有真核細胞中是為了細胞質恆定的高度保留的降解過程,而細胞自噬與細胞凋亡間的機能相關性是很複雜的。近來研究已經顯示細胞自噬對於先天免疫的調控很重要,並且類鐸受體 ( Toll-like receptor, TLR ) 接合子在巨噬細胞中能誘發細胞自噬。此外,類鐸受體接合子已經被證實在 B 細胞中能抑制消 B 細胞抗原接受器 ( B cell antigen receptor, BCR ) 活化所誘發細胞凋亡的進行,此為抑制消除自體活化之 B 細胞的重要機制。然而,在 B 細胞中類鐸受體接合子是否能誘發細胞自噬,及類鐸受體接合子誘發細胞自噬對 B 細胞抗原接受器活化誘發之細胞凋亡之生物意義還是未知。在此研究中,我們發現兩種人工合成的類鐸受體 7 接合子:Imiquimod 和 Resiquimod,皆可誘發 Ramos B細胞株的細胞自噬。此外,在 Ramos B 細胞株中 Imiquimod 與 Resiquimod 誘發的細胞自噬能拯救透過anti-IgM μ-chain抗體與 B 細胞抗原接受器結合引發的細胞凋亡,而且當細胞自噬藉由藥物 3-MA 或 Bafilomycin A1 抑制後消除了這個保護效果。這個結果不但闡明類鐸受體接合子及其所誘發之細胞自噬在 B 細胞抗原接受器活化誘發凋亡所扮演的角色,也讓我們能更深入的檢視自體免疫疾病的可能發生機制,亦希望能由此機制為基礎在未來發展出可能的預防及治療方式。
Autophagy is a highly conserved degradative process for cellular maintenance in all eukaryotic cells and its functional relationship with apoptosis is complex. Recent studies have shown that autophagy is important for the regulation of innate immunity and Toll-like receptor ( TLR ) ligands are potent autophagy inducers in macrophage. In addition, TLR ligands have been demonstrated to protect B cells from B cell antigen receptor ( BCR ) mediated apoptosis, an important mechanism to eliminate the autoreactive B cells. However, whether the TLR ligands could induce the autophagy in B cells and the biological significance of TLR induced autophagy in BCR mediated apoptosis is still unknown. In this study, we found that Imiquimod and Resiquimod, two synthetic TLR7 ligands, could induce autophagy in Ramos B cells. Moreover, Imiquimod and Resiquimod induced autophagy could rescue BCR mediated apoptosis via cross-linking with anti-IgM μ-chain antibodies in Ramos B cells and this protect effect was disrupted when autophagy was inhibited by 3-MA or Bafilomycin A1. These results not only presented a model for TLR-induced autophagy in BCR mediated apoptosis but also provided insight into the pathogenesis of autoimmune disease and a way of developing novel therapies.
其他識別: U0005-1808201113413500
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