Mechanisms for regulation of excessive host responses to LPS

脂多糖（lipopolaccharide， LPS）是革兰氏阴性菌的细胞壁成分，被宿主免疫细胞TLR4识别，激活先天免疫，对宿主产生有益作用。然而，LPS对免疫反应的激活有时会非常强烈，从而对宿主产生有害影响。在本研究中，研究了防止这种过度激活的调节机制。LPS的活性通过多种介质的作用来表达。IL-12是一种具有代表性的脂多糖介质，其本身在适当产生时具有有益作用，而在过量产生时则具有有害作用。我们已经发现了lps诱导IL-12产生的调控机制，该机制激活了IL-12p40基因启动子区域的抑制元件GA-12。结果表明，在激活GA-12之前，需要通过TLR4激活ERK通路。当小鼠腹膜渗出细胞受到高剂量LPS （1,000 ng/ml）刺激时，观察到该途径的激活，IL-12p40的产生比最佳LPS （10 ng/ml）刺激时减少。这些结果表明，这种调节机制在控制IL-12过量产生方面起着普遍的作用。我们还发现了一种天然的lps拮抗剂。在27℃（最适生长温度）培养的耶尔森氏菌获得的LPS对人体细胞有活性，而在37℃（宿主体温）培养的细菌获得的LPS对人体细胞无活性，表现出较强的拮抗活性。与LPS-27℃相比，LPS-37℃的脂质A部分的酰基数量减少。该拮抗型LPS-37℃可能通过干扰TLR4二聚化抑制TLR4下游的所有信号。研究LPS信号传导的起始步骤和每个LPS介质产生的下游步骤的抑制机制可能有助于制定针对有害LPS作用的预防措施。

Lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria, is recognized by TLR4 on host immune cells to activate innate immunity leading to beneficial effects to the host. However, activation of immune reactions by LPS sometimes proceeds so strong that harmful effects are induced to the host. In the present study, regulatory mechanisms to prevent such over-activations were investigated.Activities of LPS are expressed via actions of various mediators. IL-12 is a representative LPS-mediator and, by itself, it exhibits beneficial effects when produced properly while harmful effects when produced too much. We have found a regulatory mechanism of LPS-induced IL-12 production that activate a repressor element, GA-12, in the promoter region of IL-12p40 gene. It was indicated that hyper-activation of ERK pathway via TLR4 is required prior to activation of GA-12. When mouse peritoneal exudate cells were stimulated with a high dose LPS (1,000 ng/ml), activation of this pathway was observed and production of IL-12p40 decreased from that of optimal LPS (10 ng/ml) stimulation. These results indicated that this regulatory mechanism is functioning generally to control excessive production of IL-12.We have also found a natural LPS-antagonist. LPS obtained from Yersinia cultured at 27℃ (optimal growth temperature) was active as LPS-agonist but LPS obtained from the bacteria cultured at 37℃ (host body temperature) was not active to human cells and showed strong antagonistic activity. Number of acyl groups in lipid A part of the LPS-37℃ was decreased from that of the LPS-27℃. This antagonistic type of the LPS-37℃ was likely to suppress all the signals downstream of TLR4 by interfering with the dimerization of TLR4.Investigations of suppressive mechanisms in both initiation steps of LPS signaling and down stream steps for production of each LPS-mediator may be useful for development of preventive measures against harmful LPS actions.