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

In Alzheimer's disease (AD), chronically activated glia contribute to neuronal dysfunction through production of neuroinflammatory molecules like interleukin (IL)-1β. 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-1β 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-1β levels, consistent with a possible mechanistic relationship between MAPK and IL-1β. 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-1β production in a concentration-dependent manner. In addition, the relative importance of each MAPK to IL-1β production depended on the activating stimulus. These data demonstrate that MAPK pathways are important for microglial IL-1β production, and suggest that different glial activators use distinct sets of signaling pathways to induce the same disease-relevant end-point in microglia.