Find in Library

Activated microglia produce superoxide anion (O2·−) and nitric oxide (NO), both of which can be neurotoxic. To identify regulatory mechanisms that might modulate over-activation of microglia, we evaluated the inhibition of microglial activation by factors secreted by hippocampal cells. Supernatants from hippocampal cell cultures (Hippocampal-Cm) prevented microglial O2·− and NO production. LAP-TGFβ1 was present in the Hippocampal-Cm as shown by immunoblot and a TGFβ1-dependent proliferation-inhibition bioassay. LAP-TGFβ1 and TGFβ activity increased in hippocampal cultures exposed to proinflammatory conditions (LPS and Interferon-gamma). The inhibition of O2·− and NO production by Hippocampal-Cm was mimicked by the addition of recombinant TGFβ1. Treating Hippocampal-Cm with an antibody against TGFβ1 to neutralize its activity eliminated its ability to inhibit O2·− and NO production. Our findings suggest that the TGFβ1 secreted by hippocampal cells modulated microglial activity. We propose that in pathological conditions, impairment of this modulatory mechanism could enhance microglia-mediated neurotoxicity.