Inhibition of lipopolysaccharide-induced microglial activation by preexposure to neurotrophin-3.
Microglia activated by neural injuries produce proinflammatory mediators, but activated microglia also appear in developing neural tissue to phagocytose cell debris resulting from programmed cell death without inducing tissue damage. Thus, factors associated with the developing CNS may modulate microglial activities. Previously we reported that pretreatment with neurotrophin-3 (NT-3), a factor known to regulate neural development, inhibits the production of proinflammatory mediators, nitric oxide (NO), tumor necrosis factor-alpha, and interleukin-1beta, in BV2 activated by inflammagen lipopolysaccharide (LPS). In this study, the inhibition of proinflammatory mediators by NT-3 pretreatment (preNT-3) in primary microglia with LPS stimulation was corroborated. Moreover, pretreatment of LPS-activated microglia with NT-3 induced a trend of reduction in phagocytotic ability. By using LPS-activated BV2 cells, we further found that reduced expression of inducible NO synthetase by preNT-3 was mediated by MAP kinase and PI3 kinase signaling pathways. Moreover, pretreatment of BV2 cells with NT-3 led to reduced levels of the p65 subunit of nucleus factor-kappaB (NFkappaB) and its DNA binding activity. Accordingly, our results indicate that preexposure of microglia to NT-3 leads to a reduced production of proinflammatory mediators in activated microglia by the induction of MAP kinase and PI3 kinase signaling, which in turn may reduce NFkappaB DNA binding activity. This suggests that an NT-enriched microenvironment may be favorable for preventing the inflammatory reaction of microglia.
Tzeng
Shun-Fen
SF
Department of Life Sciences, National Cheng Kung University, Tainan, Taiwan. stzeng@mail.ncku.eud.tw
Huang
Hsin-Ying
HY
Lee
Tsung-I
TI
Jwo
Jeng-Kuan
JK
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D018836:Inflammation Mediators / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D020933:Neurotrophin 3 / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D018836:Inflammation Mediators; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D020933:Neurotrophin 3; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases