Abstract
Accumulating evidence indicates that activated microglia contribute to the neuropathology involved in many neurodegenerative diseases and after traumatic injury to the CNS. The cytokine transforming growth factor-beta 1 (TGF-β1), a potent deactivator of microglia, should have the potential to reduce microglial-mediated neurodegeneration. It is therefore perplexing that high levels of TGF-β1 are found in conditions where microglia are chronically activated. We hypothesized that TGF-β1 signaling is suppressed in activated microglia. We therefore activated primary rat microglia with lipopolysaccharide (LPS) and determined the expression of proteins important to TGF-β1 signaling. We found that LPS treatment decreased the expression of the TGF-β receptors, TβR1 and TβR2, and reduced protein levels of Smad2, a key mediator of TGF-β signaling. LPS treatment also antagonized the ability of TGF-β to suppress expression of pro-inflammatory cytokines and to induce microglial cell death. LPS treatment similarly inhibited the ability of the TGF-β related cytokine, Activin-A, to down-regulate expression of pro-inflammatory cytokines and to induce microglial cell death. Together, these data suggest that microglial activators may oppose the actions of TGF-β1, ensuring continued microglial activation and survival that eventually may contribute to the neurodegeneration prevalent in chronic neuroinflammatory conditions.