Importance of MAPK pathways for microglial pro-inflammatory cytokine IL-1 beta production.
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.
Kim
Seon H
SH
Drug Discovery Program, Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Ward 4-202, Chicago, IL 60611-3008, USA. vaneldik@northwestern.edu
Smith
Carolyn J
CJ
Van Eldik
Linda J
LJ
D000818:Animals; D002417:Cattle; D002460:Cell Line; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology; D051381:Rats; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D007375:Interleukin-1; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579159:S100b protein, mouse; C579158:S100b protein, rat; D020928:Mitogen-Activated Protein Kinases