Chelvarajan R Lakshman, Liu Yushu, Popa Diana, Getchell Marilyn L, Getchell Thomas V, Stromberg Arnold J, Bondada Subbarao
Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA.
J Leukoc Biol. 2006 Jun;79(6):1314-27. doi: 10.1189/jlb.0106024. Epub 2006 Apr 7.
Aged humans and rodents are susceptible 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 (Mphi) from aged mice. To understand the molecular basis of cytokine dysregulation in aged mouse Mphi, a microarray analysis was performed on RNA from resting and lipopolysaccharide (LPS)-stimulated Mphi 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 Mphi. Accordingly, expression of Il1 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-kappaB 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 Mphi and reduced IL-10 levels, indicating that increased p38 MAPK activity has a role in cytokine dysregulation in the aged mouse Mphi.
由于无法产生针对荚膜多糖的抗体，老年人类和啮齿动物易受肺炎链球菌感染。这部分是由于老年小鼠巨噬细胞（Mphi）产生促炎细胞因子减少以及白细胞介素（IL）-10产生增加所致。为了了解老年小鼠Mphi中细胞因子失调的分子基础，使用Affymetrix 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Mphi的RNA进行了微阵列分析。双向方差分析表明，在总体P <0.01水平下，853个基因受LPS调控（仅年轻小鼠中有169个，仅老年小鼠中有184个，两者中均有500个）。系统探索者的表达分析显示，老年小鼠Mphi中免疫反应（促炎趋化因子、细胞因子及其受体）和信号转导基因特异性降低。因此，Il1和Il6的表达降低，Il10的表达增加，证实了我们之前的结果。干扰素-γ的表达也降低。导致核因子-κB激活的Toll样受体信号通路中的基因也下调，但该通路的负调节因子IL-1受体相关激酶3在老年小鼠中增加。观察到p38丝裂原活化蛋白激酶（MAPK）基因的表达增加，蛋白质表达和酶活性相应增加，经蛋白质印迹法证实。低剂量的p38 MAPK抑制剂（SB203580）增强了Mphi产生促炎细胞因子的能力并降低了IL-10水平，表明p38 MAPK活性增加在老年小鼠Mphi的细胞因子失调中起作用。
