TNF-α-sensitive brain pericytes activate microglia by releasing IL-6 through cooperation between IκB-NFκB and JAK-STAT3 pathways

Autor: Izzettin Hatip-Al-Khatib, Funda F. Bölükbaşı Hatip, Junichi Matsumoto, Fuyuko Takata, Takashi Machida, Yasufumi Kataoka, Shinya Dohgu, Atsushi Yamauchi
Rok vydání: 2018
Předmět:
0301 basic medicine
Animals
Brain/*cytology
Cells
Cultured
Dose-Response Relationship
Drug
Enzyme Inhibitors/pharmacology
Gene Expression Regulation/drug effects
I-kappa B Proteins/metabolism
Interleukin-6/*metabolism
Mice
Microglia/*drug effects
NF-kappa B
Pericytes/*drug effects
RNA
Messenger/metabolism
Rats
Rats
Wistar
STAT3 Transcription Factor/metabolism
Signal Transduction/*drug effects
Tumor Necrosis Factor-alpha/*pharmacology
microglia
animal cell
Wistar rat
STAT3
I kappa B
NF?B
0302 clinical medicine
dose response
pericyte
rat
animal
Enzyme Inhibitors
primary culture
Microglia
biology
messenger RNA
Chemistry
brain pericyte
General Neuroscience
drug effect
neutralizing antibody
Brain
Interleukin
gene expression regulation
Tumor necrosis factor-α
cell activation
Cell biology
immunoglobulin enhancer binding protein
medicine.anatomical_structure
cytokine release
priority journal
Tumor necrosis factor-?
JAK-STAT signaling
I-kappa B Proteins
Tumor necrosis factor alpha
Pericyte
Tyrosine kinase
signal transduction
Signal Transduction
Astrocyte
STAT3 Transcription Factor
tumor necrosis factor
animal experiment
central nervous system disease
enzyme inhibitor
interleukin 6
Article
03 medical and health sciences
STAT3 protein
medicine
RNA
Messenger
Molecular Biology
mouse
Neuroinflammation
cell culture
nonhuman
Interleukin-6
Tumor Necrosis Factor-alpha
animal cell culture
protein phosphorylation
030104 developmental biology
receptor cross-talk
Gene Expression Regulation
gene expression
cytology
biology.protein
Neurology (clinical)
Pericytes
metabolism
Janus kinase
030217 neurology & neurosurgery
NFκB
Developmental Biology
Zdroj: Brain Research. 1692:34-44
ISSN: 0006-8993
Popis: Interleukin (IL)-6 is an important mediator of neurovascular dysfunction, neurodegeneration and/or neuroinflammation. We previously reported that brain pericytes released higher levels of IL-6 than did glial cells (astrocytes and microglia) in response to tumor necrosis factor (TNF)-?. Moreover, pericytes stimulated with TNF-? enhanced activation of BV-2 microglia. In this study, we investigated the mechanisms of TNF-? mediated induction of IL-6 release from brain pericytes and astrocytes and whether pericyte-derived IL-6 would facilitate activation of BV-2 microglia. Using rat brain pericyte and astrocyte primary cultures and pharmacological inhibitors, we found that, TNF-? induced the highest levels of IL-6 release from pericytes by activating the inhibitor kappa B (I?B)-nuclear factor kappa-light-chain-enhancer of activated B cells (NF?B) and Janus family of tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT)3 pathways. STAT3 contributed to TNF-? induced nuclear translocation of phospho-NF?B in pericytes. TNF-?-induced IL-6 release in astrocytes was mediated by NF?B but not by STAT3. The presence of pericytes amplified TNF-?-induced iNOS mRNA expression in BV-2 microglia. This effect was blocked by a neutralizing antibody for IL-6. These findings indicated that crosstalk between the I?B-NF?B and JAK-STAT3 pathways is a pericyte specific mechanism, not occurring in astrocytes, for TNF-?-induced IL-6 release. IL-6 derived from pericytes enhanced microglial activation. Our findings increase understanding of the role of pericyte-microglia crosstalk in the brain under neuroinflammatory conditions and suggest a potentially attractive therapeutic target for brain inflammation. © 2018 Elsevier B.V.
Databáze: OpenAIRE
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