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.
|Number of pages||9|
|Journal||Neurobiology of Aging|
|State||Published - Apr 2004|
Bibliographical noteFunding Information:
These studies were supported in part by NIH grants R37 AG13939, R01 AG20243, and P01 AG21184. S.H.K. is a postdoctoral scholar in the Drug Discovery Training Program supported by NIH grant T32 AG00260.
- MAP kinase
ASJC Scopus subject areas
- Neuroscience (all)
- Clinical Neurology
- Developmental Biology
- Geriatrics and Gerontology