Aging negatively skews macrophage TLR2- and TLR4-mediated pro-inflammatory responses without affecting the IL-2-stimulated pathway.
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.
Boehmer
Eric D
ED
Department of Cell Biology, Neurobiology and Anatomy, Loyola University Medical Center, 2160 South 1st Avenue, Maywood, IL 60153, USA.
Meehan
Michael J
MJ
Cutro
Brent T
BT
Kovacs
Elizabeth J
EJ
D000375:Aging; D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D007376:Interleukin-2; D015850:Interleukin-6; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D048051:p38 Mitogen-Activated Protein Kinases