Molecular basis of age-associated cytokine dysregulation in LPS-stimulated macrophages
Molecular basis of age-associated cytokine dysregulation in LPS-stimulated macrophages
复制标题
DOI：
10.1189/jlb.0106024
复制
发表时间：
2006-06-01
影响因子：
5.5
通讯作者：
Bondada, Subbarao
中科院分区：
文献类型：
--
作者：
Chelvarajan, R. Lakshman;Liu, Yushu;Bondada, Subbarao
老年人和啮齿类动物由于不能产生针对荚膜多糖的抗体而不易感染肺炎链球菌。这部分是由于促炎细胞因子的产生减少和老年小鼠巨噬细胞（M Phi）产生的白细胞介素（IL）-10增加。为了了解老年小鼠M Phi中细胞因子失调的分子基础，使用Affytelium Mouse Genome 430 2.0基因芯片对来自老年和对照小鼠的静息和脂多糖（LPS）刺激的M Phi的RNA进行微阵列分析。双因素方差分析表明，在总体P < 0.01的水平上，853个基因受LPS调控（仅年轻人中169个，仅老年人中184个，两者中均为500个）。系统探索者的表达分析显示，免疫反应（促炎趋化因子，细胞因子，及其受体）和信号转导基因在老年小鼠M Phi中特异性降低。因此，Ill和Il 6的表达减少，而Il 10增加，证实了我们先前的结果。干扰素-γ的表达也减少。Toll样受体信号通路中导致核因子-κ B活化的基因也下调，但IL-1受体相关激酶3（该通路的负调节因子）在老年小鼠中增加。观察到p38丝裂原活化蛋白激酶（MAPK）基因表达增加，蛋白质表达和酶活性相应增加，并通过Western印迹法证实。低剂量的p38 MAPK抑制剂（SB 203580）增强了M Phi的促炎细胞因子产生并降低了IL-10水平，表明p38 MAPK活性增加在老年小鼠M Phi中的细胞因子失调中起作用。
Aged humans and rodents are susceptihle to infection with Streptococcus pneumoniae bacteria as a result of an inability to make antibodies to capsular polysaccharides. This is partly a result of decreased production of proinflammatory cytokines and increased production of interleukin (IL)-10 by macrophages (M Phi) from aged mice. To understand the molecular basis of cytokine dysregulation in aged mouse M Phi, a microarray analysis was performed on RNA from resting and lipopolysaccharide (LPS)-stimulated M Phi from aged and control mice using the Affymetrix Mouse Genome 430 2.0 gene chip. Two-way ANOVA analysis demonstrated that at an overall P < 0.01 level, 853 genes were regulated by LPS (169 in only the young, 184 in only the aged, and 500 in both). Expression analysis of systematic explorer revealed that immune response (proinflammatory chemokines, cytokines, and their receptors) and signal transduction genes were specifically reduced in aged mouse M Phi. Accordingly, expression of IlI and Il6 was reduced, and Il10 was increased, confirming our previous results. There was also decreased expression of interferon-gamma. Genes in the Toll-like receptor-signaling pathway leading to nuclear factor-kappa B activation were also down-regulated but IL-1 receptor-associated kinase 3, a negative regulator of this pathway, was increased in aged mice. An increase in expression of the gene for p38 mitogen-activated protein kinase (MAPK) was observed with a corresponding increase in protein expression and enzyme activity confirmed by Western blotting. Low doses of a p38 MAPK inhibitor (SB203580) enhanced proinflammatory cytokine production by M Phi and reduced IL-10 levels, indicating that increased p38 MAPK activity has a role in cytokine dysregulation in the aged mouse M Phi.