Importance of MAPK pathways for microglial pro-inflammatory cytokine IL-1 beta production

Neurobiol Aging. 2004 Apr;25(4):431-9. doi: 10.1016/S0197-4580(03)00126-X.


In Alzheimer's disease (AD), chronically activated glia contribute to neuronal dysfunction through production of neuroinflammatory molecules like interleukin (IL)-1beta. As a first step to address the signaling pathways important for pro-inflammatory cytokine induction, and whether different activators use distinct pathways, we tested the involvement of mitogen-activated protein kinase (MAPK) pathways in microglial IL-1beta production. Microglial cultures stimulated with lipopolysaccharide, S100B, or beta-amyloid showed rapid activation of three different MAPKs (p38, ERK1/2, and JNK) and a later increase in IL-1beta levels, consistent with a possible mechanistic relationship between MAPK and IL-1beta. To more directly test this possibility, we stimulated microglia in the presence of selective MAPK inhibitors, and found that inhibition of each of the three MAPK pathways inhibited IL-1beta production in a concentration-dependent manner. In addition, the relative importance of each MAPK to IL-1beta production depended on the activating stimulus. These data demonstrate that MAPK pathways are important for microglial IL-1beta production, and suggest that different glial activators use distinct sets of signaling pathways to induce the same disease-relevant end-point in microglia.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cattle
  • Cell Line
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / metabolism
  • Inflammation Mediators / physiology*
  • Interleukin-1 / antagonists & inhibitors
  • Interleukin-1 / biosynthesis
  • Interleukin-1 / metabolism
  • Interleukin-1 / physiology*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Microglia / drug effects
  • Microglia / enzymology
  • Microglia / metabolism*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Nerve Growth Factors / pharmacology
  • Rats
  • S100 Calcium Binding Protein beta Subunit
  • S100 Proteins / pharmacology


  • Enzyme Inhibitors
  • Inflammation Mediators
  • Interleukin-1
  • Nerve Growth Factors
  • S100 Calcium Binding Protein beta Subunit
  • S100 Proteins
  • S100b protein, mouse
  • S100b protein, rat
  • Mitogen-Activated Protein Kinases