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Because these conditions involve proinflammatory signaling through toll-like receptors (TLRs), we examined the effects of 3\u03b1,5\u03b1-THP, and pregnenolone on TLR4 activation in both the periphery and the central nervous system (CNS). We used monocytes\/macrophages (RAW264.7) as a model of peripheral immune signaling and studied innately activated TLR4 in the ventral tegmental area (VTA) of selectively bred alcohol-preferring (P) rats. LPS activated the TLR4 pathway in RAW264.7 cells as evidenced by increased levels of p-TAK1, TRAF6, NF-\u03baB p50, phospho-NF-\u03baB- p65, pCREB, HMGB1, and inflammatory mediators, including MCP-1 and TNF\u03b1. Both 3\u03b1,5\u03b1-THP and pregnenolone (0.5\u20131.0\u03bcM) substantially (~80%) inhibited these effects, indicating pronounced inhibition of TLR4 signaling. The mechanism of inhibition appears to involve blockade of TLR4\/MD-2 protein interactions in RAW246.7 cells. In VTA, 3\u03b1,5\u03b1-THP (15\u2009mg\/kg, IP) administration reduced TRAF6 (~20%), CRF (~30%), and MCP-1 (~20%) levels, as well as TLR4 binding to GABA<jats:sub>A<\/jats:sub> receptor\u00a0\u03b12 subunits (~60%) and MyD88 (~40%). The data suggest that inhibition of proinflammatory neuroimmune signaling underlies protective effects of 3\u03b1,5\u03b1-THP in immune cells and brain, apparently involving blocking of protein-protein interactions that initiate TLR4-dependent signaling. Inhibition of pro-inflammatory TLR4 activation represents a new mechanism of 3\u03b1,5\u03b1-THP action in the periphery and the brain.<\/jats:p>","DOI":"10.1038\/s41598-018-37409-6","type":"journal-article","created":{"date-parts":[[2019,2,4]],"date-time":"2019-02-04T11:04:09Z","timestamp":1549278249000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":115,"title":["Endogenous Neurosteroid (3\u03b1,5\u03b1)3-Hydroxypregnan-20-one Inhibits Toll-like-4 Receptor Activation and Pro-inflammatory Signaling in Macrophages and Brain"],"prefix":"10.1038","volume":"9","author":[{"given":"Irina","family":"Balan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew C.","family":"Beattie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8723-734X","authenticated-orcid":false,"given":"Todd K.","family":"O\u2019Buckley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Aurelian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4441-956X","authenticated-orcid":false,"given":"A. 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