Role of phosphoinositide 3-kinase-Akt signaling pathway in the age-related cytokine dysregulation in splenic macrophages stimulated via TLR-2 or TLR-4 receptors.
Role of phosphoinositide 3-kinase-Akt signaling pathway in the age-related cytokine dysregulation in splenic macrophages stimulated via TLR-2 or TLR-4 receptors.
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DOI：
10.1016/j.mad.2011.05.003
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发表时间：
2011-06
影响因子：
5.3
通讯作者：
Bondada, Subbarao
中科院分区：
文献类型：
--
作者：
Fallah, Mosoka P.;Chelvarajan, R. Lakshman;Garvy, Beth A.;Bondada, Subbarao
关键词：
老年人B淋巴细胞和巨噬细胞中的炎症相关缺陷导致疫苗对许多革兰氏阳性细菌如肺炎链球菌的效力降低。来自老年小鼠的脾巨噬细胞已显示在促炎细胞因子（IL-6、IL-12、IL-1β、TNF-α）的产生方面具有缺陷，但在TLR 4连接后表现出IL-10的产生增加。我们发现，衰老的巨噬细胞在TLR 2配体或杀死的S.肺炎。我们推测，与年龄相关的磷脂酰肌醇3-激酶（PI 3 K）-Akt信号通路活性的增加可能在与年龄相关的细胞因子失调中发挥因果作用。我们发现，老年人脾巨噬细胞IA类PI 3 K的调节亚基（p85β）和催化亚基（p110δ）的基因表达均高于年轻人。P-Akt及其下游靶标糖原合成酶激酶-3（GSK-3）的上调也证明了与年龄相关的PI 3 K活性增加。PI 3 K的抑制增强了TLR-2/TLR-1、TLR-2/TLR-6和TLR-4配体对促炎细胞因子的诱导，以及热杀死S. pneumoniae（HKSP）。因此，靶向PI 3-激酶可以挽救衰老巨噬细胞中的细胞因子失调，并增强支持B细胞活化和分化所需的相关促炎细胞因子。
Age-associated defects in both B-lymphocytes and macrophages in elderly result in a reduction in the efficacy of vaccines to many Gram positive bacteria like Streptococcus pneumoniae. Splenic macrophages from aged mice have been shown to have a defect in production of pro-inflammatory cytokines (IL-6, IL-12, IL-1β, TNF-α) but exhibit increased production of IL-10 upon TLR4 ligation. Here we showed that aged macrophages demonstrate similar cytokine dysregulation phenotype upon stimulation with TLR2 ligands, or killed S. pneumoniae. We hypothesized that an age-associated increase in activity of phosphatidyl inositol 3-kinase (PI3K)-Akt signaling pathway may be playing a causal role in the age-associated cytokine dysregulation. We found that gene expression of both the regulatory (p85β) and the catalytic (p110δ) subunits of Class IA PI3K is higher in aged than in young splenic macrophages. The age-associated increase in the activity of PI3K was also demonstrated by an upregulation of P-Akt and its downstream target, glycogen synthase kinase-3 (GSK-3). Inhibition of PI3K enhanced induction of pro-inflammatory cytokines, by TLR-2/TLR-1, TLR-2/TLR-6 and TLR-4 ligands as well as heat killed S. pneumoniae (HKSP). Therefore, targeting PI3-Kinase could rescue cytokine dysregulation in aged macrophages and enhance the relevant pro-inflammatory cytokines needed to support B-cell activation and differentiation.
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影响因子：
4.6
作者：
Gomez CR;Karavitis J;Palmer JL;Faunce DE;Ramirez L;Nomellini V;Kovacs EJ
通讯作者：
Kovacs EJ
影响因子：
3.1
作者：
Garg, M;Luo, W;Bondada, S
通讯作者：
Bondada, S
影响因子：
5.5
作者：
Farhat, Katja;Riekenberg, Sabine;Ulmer, Artur J.
通讯作者：
Ulmer, Artur J.
影响因子：
5.5
作者：
Bondada, S;Wu, HJ;Chelvarajan, RL
通讯作者：
Chelvarajan, RL
影响因子：
16.8
作者：
Fukao, T;Koyasu, S
通讯作者：
Koyasu, S