title: SMAD4 is Involved in the Development of Endotoxin Tolerance in Microglia.
abstract: Initial exposure of macrophages to LPS induces hyporesponsiveness to a second challenge with LPS, a phenomenon termed LPS tolerance. Smad4 plays important roles in the induction of LPS tolerance. However, the function of Smad4 in microglia remains unknown. Here we show that expression of Smad4 was highly up-regulated in LPS-tolerized mouse cerebral cortex. Smad4 was mostly colocalized with microglia, rarely with neurons. Using a microglia cell line, BV2, we find that LPS activates endogenous Smad4, inducing its migration into the nucleus and increasing its expression. Smad4 significantly suppressed TLR-triggered production of proinflammatory cytokines (IL-6), increased anti-inflammatory cytokine in LPS-tolerized microglia. Moreover, IL-6 concentrations in culture supernatants after second LPS challenge are higher in SMAD4 small interfering RNA (siRNA) BV2 cells than control siRNA BV2 cells, indicating failure to induce tolerance in absence of Smad4 signaling. In our study, we conclude that both in vivo and in vitro, Smad4 signaling is required for maximal induction of endotoxin tolerance.
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, Nantong, 226001, China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong, 226001, Chcina.|Department of Pathogen Biology, Medical College of Nantong University, Nantong, 226001, China.
authors.forename: Yongwei
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, Nantong, 226001, China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Dai
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, Nantong, 226001, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong, 226001, Chcina.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Xue
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, Nantong, 226001, China.
authors.forename: Haidan
authors.initials: H
authors.lastname: Ni
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, Nantong, 226001, China.
authors.forename: Lijian
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, Nantong, 226001, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong, 226001, Chcina.
authors.forename: Debin
authors.initials: D
authors.lastname: Yuan
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong, 226001, Chcina. nttaotao@ntu.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Tao
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, Nantong, 226001, China. cmhongnt@sina.com.
authors.forename: Maohong
authors.initials: M
authors.lastname: Cao
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004731:Endotoxins / Q000494:pharmacology*; D007108:Immune Tolerance / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051901:Smad4 Protein / Q000378:metabolism*
chemical_list: D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides; D051901:Smad4 Protein; C490810:Smad4 protein, mouse
keywords: Endotoxin tolerance; LPS; Microglia; Smad4