Aging negatively skews macrophage TLR2- and TLR4-mediated pro-inflammatory responses without affecting the IL-2-stimulated pathway

Mech Ageing Dev. 2005 Dec;126(12):1305-13. doi: 10.1016/j.mad.2005.07.009. Epub 2005 Sep 8.


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 (JNK) 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-2Rbeta. 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)-kappaB 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animals
  • Blotting, Western
  • Cell Membrane / metabolism
  • Cytokines / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Inflammation*
  • Interleukin-10 / metabolism
  • Interleukin-2 / genetics*
  • Interleukin-2 / metabolism
  • Interleukin-6 / metabolism
  • Ligands
  • Lipopolysaccharides / metabolism
  • MAP Kinase Signaling System
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred BALB C
  • NF-kappa B / metabolism
  • Phosphorylation
  • Signal Transduction
  • Time Factors
  • Toll-Like Receptor 2 / genetics*
  • Toll-Like Receptor 4 / genetics*
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Cytokines
  • Interleukin-2
  • Interleukin-6
  • Ligands
  • Lipopolysaccharides
  • NF-kappa B
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • p38 Mitogen-Activated Protein Kinases