Sustained anti-inflammatory effects of TGF-β1 on microglia/macrophages

Ischemic brain injuries caused release of damage-associated molecular patterns (DAMPs) that activate microglia/macrophages (MG/MPs) by binding to Toll-like receptors. Using middle cerebral artery transiently occluded rats, we confirmed that MG/MPs expressed inducible nitric oxide synthase (iNOS) on...

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Published in:	Biochimica et biophysica acta. Molecular basis of disease 2018-03, Vol.1864 (3), p.721-734
Main Authors:	Islam, Afsana, Choudhury, Mohammed Emamussalehin, Kigami, Yuka, Utsunomiya, Ryo, Matsumoto, Shirabe, Watanabe, Hideaki, Kumon, Yoshiaki, Kunieda, Takeharu, Yano, Hajime, Tanaka, Junya
Format:	Article
Language:	eng
Subjects:	Animals Brain ischemia Cells, Cultured Infarction, Middle Cerebral Artery - immunology Infarction, Middle Cerebral Artery - metabolism Infarction, Middle Cerebral Artery - pathology Inflammation - chemically induced Inflammation - prevention & control iNOS Interferon regulatory factor 1 Interleukin-4 IκB kinase Lipopolysaccharides Macrophages - drug effects Macrophages - metabolism Macrophages - pathology Male Microglia - drug effects Microglia - metabolism Microglia - pathology NFκB Rats Rats, Wistar Signal Transduction - drug effects Transforming Growth Factor beta1 - pharmacology
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Summary:	Ischemic brain injuries caused release of damage-associated molecular patterns (DAMPs) that activate microglia/macrophages (MG/MPs) by binding to Toll-like receptors. Using middle cerebral artery transiently occluded rats, we confirmed that MG/MPs expressed inducible nitric oxide synthase (iNOS) on 3days after reperfusion (dpr) in ischemic rat brain. iNOS expression almost disappeared on 7dpr when transforming growth factor-β1 (TGF-β1) expression was robustly increased. After transient incubation with TGF-β1 for 24h, rat primary microglial cells were incubated with lipopolysaccharide (LPS) and released NO level was measured. The NO release was persistently suppressed even 72h after removal of TGF-β1. The sustained TGF-β1 effects were not attributable to microglia-derived endogenous TGF-β1, as revealed by TGF-β1 knockdown and in vitro quantification studies. Then, boiled supernatants prepared from ischemic brain tissues showed the similar sustained inhibitory effects on LPS-treated microglial cells that were prevented by the TGF-β1 receptor-selective blocker SB525334. After incubation with TGF-β1 for 24h and its subsequent removal, LPS-induced phosphorylation of IκB kinases (IKKs), IκB degradation, and NFκB nuclear translocation were inhibited in a sustained manner. SB525334 abolished all these effects of TGF-β1. In consistent with the in vitro results, phosphorylated IKK-immunoreactivity was abundant in MG/MPs in ischemic brain lesion on 3dpr, whereas it was almost disappeared on 7dpr. The findings suggest that abundantly produced TGF-β1 in ischemic brain displays sustained anti-inflammatory effects on microglial cells by persistently inhibiting endogenous Toll-like receptor ligand-induced IκB degradation. [Display omitted] •Microglia/macrophages in ischemic brain express iNOS only at the early phase.•High expression of TGF-β1 was observed at the later phase of the ischemic event.•Once incubated with TGF-β1, cultured microglia became unresponsive to LPS.•The inhibitory TGF-β1 effects were sustained for days after its removal.•TGF-β1 caused sustained inhibition of LPS-induced IKK phosphorylation.
ISSN:	0925-4439 1879-260X