title: LPS antagonism of TGF-β signaling results in prolonged survival and activation of rat primary microglia.
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.
authors.affiliation: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Kendall
authors.initials: K
authors.lastname: Mitchell
authors.forename: Jill P
authors.initials: JP
authors.lastname: Shah
authors.forename: Lyubov V
authors.initials: LV
authors.lastname: Tsytsikova
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Campbell
authors.forename: Kwame
authors.initials: K
authors.lastname: Affram
authors.forename: Aviva J
authors.initials: AJ
authors.lastname: Symes
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta
keywords: LPS/TLR4; TGF-β; cytokines; inflammation; microglia; smad signaling