123(P-80) 緑膿菌クオラムセンシング関連分子のホスト細胞への影響(ポスター発表の部)

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Quorum-sensing is a bacterial intercellular communication device for controlling gene expression in response to cell population density through production of a small signal molecule, called an autoinducer. Pseudomonas aeruginosa have at least two autoinducers, N-3-oxododecanoyl-L-homoserine lactone (3-oxo-C_<12>-HSL) and N-butanoyl-L-homoserine lactone (C_4-HSL), to regulate gene expression of a panel of virulence factors. Current progress in this field demonstrated that 3-oxo-C_<12>-HSL has an immunomodulatory activity, such as induction of IL-8 and prostaglandin-E. Recently, we have reported that 3-oxo-C_<12>-HSL, but not C_4-HSL induces apoptosis in eukaryotic cells. Interestingly, induction of apoptosis was observed in macrophages (U937, P388D1), neutrophils, but not fibroblast (L-cell) nor epithelial cells (CCL-185, HEp-2), although molecular mechanisms of this phenomenon are largely unknown. In the present study, we synthesized an array of homoserine lactone analogs to characterize critical structures of autoinducer and cellular target(s) for induction of apoptosis in macrophage P388D1. The data of structure-activity correlation demonstrated that 3-oxo group in acyl-chain and L-form-homoserine lactone ling were critical for apoptosis-inducing activity. Additionally, length of acyl-chain appears to be important although analogs containing longer acyl-side chain than 3-oxo-C_<12>-HSL are still active. In contrast, alteration of hydrophobicity in acyl-chain, such as 12-hydroxy-3-oxo-C_<12>-HSL, induced loss of activity whereas sterically hindered and hydrophobic groups, such as phenyl or cyclopropyl group, kept apoptosis-inducing activity. Our data demonstrated that fine structures of 3-oxo-C_<12>-HSL, such as 3-oxo, length of acyl-side chain and hydrophobicity, are crucial for apoptosis-inducing activity, which suggests presence of putative receptor(s) in eukaryotic cells. Further investigations to find out molecular target(s) of 3-oxo-C_<12>-HSL are ongoing not only for induction of apoptosis in macrophages, but also for production of IL-8 in epithelial cells.
天然有機化合物討論会の論文
2004-10-01

123(P-80) 緑膿菌クオラムセンシング関連分子のホスト細胞への影響(ポスター発表の部)

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