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Background  Ethanol (EtOH) consumption leads to an increase of proinflammatory signaling via activation of Toll‐like receptors ( TLR s) such as  TLR 3 and  TLR 4 that leads to kinase activation ( ERK 1/2, p38,  TBK 1), transcription factor activation ( NF  κ B,  IRF 3), and increased transcription of proinflammatory cytokines such as  TNF ‐ α ,  IL ‐1 β , and  IL ‐6. This immune signaling cascade is thought to play a role in neurodegeneration and alcohol use disorders. While microglia are considered to be the primary macrophage in brain, it is unclear what if any role neurons play in EtOH‐induced proinflammatory signaling.    Methods  Microglia‐like  BV 2 and retinoic acid‐differentiated neuron‐like  SH ‐ SY 5Y were treated with  TLR 3 agonist Poly(I:C),  TLR 4 agonist lipopolysaccharide ( LPS ), or Et OH  for 10 or 30 minutes to examine proinflammatory immune signaling kinase and transcription factor activation using Western blot, and for 24 hours to examine induction of proinflammatory gene  mRNA  using  RT ‐ PCR .    Results  In  BV 2, both  LPS  and Poly(I:C) increased p‐ ERK 1/2, p‐p38, and p‐ NF  κ B by 30 minutes, whereas Et OH  decreased p‐ ERK 1/2 and increased p‐ IRF 3.  LPS , Poly(I:C), and Et OH  all increased  TNF ‐ α  and  IL ‐1 β   mRNA , and Et OH  further increased  TLR 2, 7, 8, and  MD ‐2  mRNA  in  BV 2. In  SH ‐ SY 5Y,  LPS  had no effect on kinase or proinflammatory gene expression. However, Poly(I:C) increased p‐p38 and p‐ IRF 3, and increased expression of  TNF ‐ α ,  IL ‐1 β , and  IL ‐6, while Et OH  increased p‐p38, p‐ IRF 3, p‐ TBK 1, and p‐ NF  κ B while decreasing p‐ ERK 1/2 and increasing expression of  TLR 3, 7, 8, and  RAGE mRNA .  HMGB 1, a  TLR  agonist, was induced by  LPS  in  BV 2 and by Et OH  in both cell types. Et OH  was more potent at inducing proinflammatory gene  mRNA  in  SH ‐ SY 5Y compared with BV2.    Conclusions  These results support a novel and unique mechanism of EtOH,  TLR 3, and  TLR 4 signaling in neuron‐like  SH ‐ SY 5Y and microglia‐like  BV 2 that likely contributes to the complexity of brain neuroimmune signaling.

Ethanol, TLR 3, and TLR 4 Agonists Have Unique Innate Immune Responses in Neuron‐Like SH ‐ SY 5Y and Microglia‐Like BV 2