Microglial Activation Results in Inhibition of TGF-β-Regulated Gene Expression

Chronic inflammation mediated by persistent microglial activation is associated with the pathogenesis of neurodegenerative diseases. The mechanisms underlying chronic microglial activation are poorly understood. We have previously shown that anti-inflammatory TGF-beta signaling is inhibited in LPS-treated microglia. In this study, we assessed whether different disease-related microglial activators could downregulate TGF-beta induction of gene expression. We examined the effects of amyloid beta (A beta) (1-42)- or heat-killed Listeria monocytogenes (HKLM) on the TGF-beta-regulated gene expression in primary rat microglia. We found that A beta (1-42) oligomers and HKLM, in addition to LPS, suppressed TGF-beta-mediated induction of gene expression in part through reducing expression of T beta R1 mRNA encoding the TGF-beta receptor 1 in primary microglia. A beta (1-42) and LPS also prevented induction of TGF-beta-induced genes in primary microglia. Additionally, A beta (1-42) rescued primary microglia from TGF-beta-mediated cell death without increasing cell proliferation. Blockage of NF kappa B signaling, but not the ERK or IRF3 pathways, inhibited A beta (1-42)- and LPS-mediated reduction of T beta R1 mRNA. Finally, LPS and A beta (1-42) induced transient upregulation of mRNAs encoding SnoN and Bambi, inhibitors of TGF-beta signaling. Our data indicate that one mechanism through which activators may prolong microglial stimulation is through direct inhibition of anti-inflammatory signaling. A more detailed understanding of the interaction between inflammatory and anti-inflammatory pathways may reveal potential targets for ameliorating chronic inflammation and hence speed the development of therapeutics to address neurodegenerative diseases.