Leptospiral hemolysins induce proinflammatory cytokines through Toll-like receptor 2-and 4-mediated JNK and NF-κB signaling pathways.
Leptospiral hemolysins induce proinflammatory cytokines through Toll-like receptor 2-and 4-mediated JNK and NF-κB signaling pathways.
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DOI：
10.1371/journal.pone.0042266
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yan J
中科院分区：
文献类型：
--
作者：
Wang H;Wu Y;Ojcius DM;Yang XF;Zhang C;Ding S;Lin X;Yan J
致病性钩端螺旋体属的感染导致患者严重的全身性炎症。虽然一些钩端螺旋体促炎分子已被确定，钩端螺旋体可能编码其他身份不明的强烈炎症刺激。致病性L.问号线虫基因组编码许多推定的溶血素基因。由于来自其他细菌的溶血素可引起炎症反应，我们假设钩端螺旋体溶血素可作为促炎刺激物，促进与钩端螺旋体感染相关的强烈炎症。我们首先使用细胞因子蛋白微阵列系统分析钩端螺旋体病患者和钩端螺旋体感染小鼠的血清细胞因子谱。结果表明，IL-1β、IL-6和TNF-α是患者和小鼠血清中主要的促炎细胞因子。然后，我们分析了八个假定的溶血素在L。赖氏菌株。结果表明，其中Sph 1、Sph 2、Sph 3、HlpA和TlyA五种蛋白均具有溶血活性。更重要的是，这五种溶血素诱导人和小鼠巨噬细胞产生大量IL-1β、IL-6和TNF-α（尽管后者略低）。此外，用抗体或NF-κB或JNK信号通路抑制剂阻断TLR 2或TLR 4可显著降低溶血素诱导的IL-1β、IL-6和TNF-α的产生。从TLR 2-、TLR 4-或双TLR 2-和TLR 4-缺陷小鼠中分离的巨噬细胞也证实了诱导促炎细胞因子的钩端螺旋体溶血素是TLR 2-和TLR 4-依赖性的。我们的研究结果表明，L。问号线虫分泌许多溶血素，其通过TLR 2-和TLR 4-依赖性JNK和NF-κB途径作为促炎细胞因子的强力诱导剂起作用。
Infection with pathogenic Leptospira species causes serious systemic inflammation in patients. Although a few leptospiral proinflammatory molecules have been identified, Leptospira likely encodes other unidentified strong inflammation stimulators. The pathogenic L. interrogans genome encodes numerous putative hemolysin genes. Since hemolysins from other bacteria can cause inflammatory reactions, we hypothesized that leptospiral hemolysins may function as proinflammatory stimulators that contribute to the strong inflammation associated with Leptospira infection. We first used cytokine protein microarrays for systematic analysis of serum cytokine profiles in leptospirosis patients and leptospire-infected mice. We found that IL-1β, IL-6 and TNF-α were the main proinflammatory cytokines in the sera of both the patients and the mice. We then analyzed eight putative hemolysins in L. interrogans strain Lai. The results showed that five of them, Sph1, Sph2, Sph3, HlpA and TlyA were secreted and had hemolytic activity. More importantly, these five hemolysins induced the strong production of IL-1β, IL-6 and TNF-α in human and mouse macrophages (although a bit lower in the latter). Furthermore, blockade of TLR2 or TLR4 with either antibodies or inhibitors of the NF-κB or JNK signaling pathways significantly reduced the production of hemolysin-induced IL-1β, IL-6 and TNF-α. Macrophages isolated from TLR2-, TLR4-or double TLR2-and 4-deficient mice also confirmed that the leptospiral hemolysins that induce proinflammatory cytokines are both TLR2-and TLR4-dependent. Our findings demonstrate that L. interrogans secretes many hemolysins that function as powerful inducers of proinflammatory cytokines through both TLR2-and TLR4-dependent JNK and NF-κB pathways.
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DOI：
10.1128/cdli.10.2.332-335.2003
发表时间：
2003-03-01
期刊：
CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY
影响因子：
--
作者：
de Fost, M;Hartskeerl, RA;van der Poll, T
通讯作者：
van der Poll, T
影响因子：
2.1
作者：
Cinco, M;Vecile, E;Dobrina, A
通讯作者：
Dobrina, A
影响因子：
3.1
作者：
Ito, Y;Kawamura, I;Mitsuyama, M
通讯作者：
Mitsuyama, M
影响因子：
3.4
作者：
Arcidiacono, Diletta;Odom, Sandra;de Bernard, Marina
通讯作者：
de Bernard, Marina
影响因子：
4.4
作者：
Chassin, Cecilia;Picardeau, Mathieu;Werts, Catherine
通讯作者：
Werts, Catherine