Aging negatively skews macrophage TLR2- and TLR4-mediated pro-inflammatory responses without affecting the IL-2-stimulated pathway
Aging negatively skews macrophage TLR2- and TLR4-mediated pro-inflammatory responses without affecting the IL-2-stimulated pathway
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DOI：
10.1016/j.mad.2005.07.009
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发表时间：
2005-12-01
影响因子：
5.3
通讯作者：
Kovacs, EJ
中科院分区：
文献类型：
--
作者：
Boehmer, ED;Meehan, MJ;Kovacs, EJ
我们最近报道，在脂多糖(LPS)刺激下，老年小鼠的巨噬细胞产生的肿瘤坏死因子(TNF)-α比年轻动物的巨噬细胞少。这与磷酸化和总p38和c-jun氨基末端激酶(INK)丝裂原激活蛋白激酶(MAPK)水平的降低有关。在这里，我们继续确定年龄是否影响其他Toll-like(TLR)和非TLR信号通路。我们发现，与年轻小鼠相比，内毒素和酵母多糖刺激的老年小鼠脾巨噬细胞产生的肿瘤坏死因子-α和白介素6减少。相反，在内毒素刺激下，老年组IL-10的产生高于青年组，而酵母多糖没有刺激老年组。相反，IL-2刺激的肿瘤坏死因子-α和IL-6的产生不受年龄的影响。与年龄相关的变化与细胞表面TLR2、TLR4或IL-2Rβ表达的变化无关。老年小鼠巨噬细胞的p38MAPK和MAPK活化蛋白激酶(APK)-2活性降低。P38蛋白表达随增龄而减少，而MAPK-APK-2蛋白表达不随增龄而减少。此外，老龄小鼠巨噬细胞暴露于脂多糖后，核因子-kappaB的活性显著降低，但IL-2未见明显变化。这些数据表明，年龄相关的巨噬细胞信号的改变是特定的途径，并提示TLR介导的途径在MAPK表达水平上随着年龄的增长而受损。(C)2005爱思唯尔爱尔兰有限公司。保留所有权利。
We recently reported that macrophages from aged mice produced less tumor necrosis factor (TNF)-alpha following lipopolysaccharide (LPS) stimulation than macrophages from young animals. This correlated with decreased levels of phosphorylated and total p38 and c-Jun N-terminal kinase (INK) mitogen-activated protein kinases (MAPKs). Here, we went on to determine if age affects other Toll-like (TLR) and non-TLR signaling pathways. We found that LPS- and zymosan- stimulated TNF-alpha and IL-6 production is attenuated in splenic macrophages from aged mice compared to young. Conversely, LPS-stimulated, but not zymosan-stimulated, IL-10 production from the aged group was elevated over that of the young group. In contrast, IL-2-stimulated TNF-alpha and IL-6 production was not affected by age. The age-associated changes did not correlate with alterations in the cell-surface expression of TLR2, TLR4, or IL-2R beta. Macrophages from aged mice demonstrated lower p38 MAPK and MAPK-activated protein kinase (APK)-2 activation. Protein expression of p38, but not MAPK-APK-2, was reduced with age. Additionally, nuclear factor (NF)-kappa B activation was significantly decreased in macrophages from aged mice after exposure to LPS, but not IL-2. These data indicate that age-associated macrophage signaling alterations are pathway-specific and suggest that TLR-mediated pathways are impaired with age at the level of MAPK expression. (c) 2005 Elsevier Ireland Ltd. All rights reserved.