Atsttrin reduces lipopolysaccharide-induced neuroinflammation by inhibiting the nuclear factor kappa B signaling pathway
| Autor: | Hua Zhao, Lei Cheng, Lian Liu, Chang-Jiao Ji, Lin Nie, Meng Si, Yuan Qu, Yi Liu, He-Cheng Ma, Ahmed Fayyaz Noor |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Lipopolysaccharide inflammatory cytokines nuclear factor kappa B signaling pathway Pharmacology cerebrospinal fluid lcsh:RC346-429 neuroinflammation Proinflammatory cytokine 03 medical and health sciences chemistry.chemical_compound astrocyte 0302 clinical medicine Developmental Neuroscience progranulin nerve regeneration Atsttrin lipopolysaccharide intracerebroventricular injection progranulin knockout mouse neural regeneration medicine lcsh:Neurology. Diseases of the nervous system Neuroinflammation biology Nitric oxide synthase 030104 developmental biology medicine.anatomical_structure chemistry Knockout mouse biology.protein Tumor necrosis factor alpha Signal transduction 030217 neurology & neurosurgery Research Article Astrocyte |
| Zdroj: | Neural Regeneration Research, Vol 14, Iss 11, Pp 1994-2002 (2019) Neural Regeneration Research |
| ISSN: | 1673-5374 |
| DOI: | 10.4103/1673-5374.259623 |
| Popis: | Progranulin is closely related to neuronal survival in a neuroinflammatory mouse model and attenuates inflammatory reactions. Atsttrin is an engineered protein composed of three progranulin fragments and has been shown to have an effect similar to that of progranulin. Atsttrin has anti-inflammatory actions in multiple arthritis mouse models, and it protects against further arthritis development. However, whether Atsttrin has a role in neuroinflammation remains to be elucidated. In this study, we produced a neuroinflammatory mouse model by intracerebroventricular injection of 1 μL lipopolysaccharide (10 μg/μL). Atsttrin (2.5 mg/kg) was administered via intraperitoneal injection every 3 days over a period of 7 days before intracerebroventricular injection of 1 μL lipopolysaccharide (10 μg/μL). In addition, astrocyte cultures were treated with 0, 100 or 300 ng/mL lipopolysaccharide, with 200 ng/mL Atsttrin simultaneously. Immunohistochemistry, enzyme-linked immunosorbent assay and real-time reverse transcription-polymerase chain reaction were performed to examine the protein and mRNA levels of inflammatory mediators and to assess activation of the nuclear factor kappa B signaling pathway. Progranulin expression in the brain of wild-type mice and in astrocyte cultures was increased after lipopolysaccharide administration. The protein and mRNA expression levels of tumor necrosis factor-α, interleukin-1β and inducible nitric oxide synthase were increased in the brain of progranulin knockout mice after lipopolysaccharide administration. Atsttrin treatment reduced the lipopolysaccharide-induced increase in the protein and mRNA levels of tumor necrosis factor-α, interleukin-1β, matrix metalloproteinase-3 and inducible nitric oxide synthase in the brain of progranulin knockout mice. Atsttrin also reduced the expression of cyclooxygenase-2, inducible nitric oxide synthase and matrix metalloproteinase 3 mRNA in lipopolysaccharide-treated astrocytes in vitro, and decreased the concentration of tumor necrosis factor a and interleukin-1β in the supernatant. Furthermore, Atsttrin significantly reduced the levels of phospho-nuclear factor kappa B inhibitor a in the brain of lipopolysaccharide-treated progranulin knockout mice and astrocytes, and it decreased the expression of nuclear factor kappa B2 in astrocytes. Collectively, our findings show that the anti-neuroinflammatory effect of Atsttrin involves inhibiton of the nuclear factor kappa B signaling pathway, and they suggest that Atsttrin may have clinical potential in neuroinflammatory therapy. The study was approved by the Animal Ethics Committee of Qilu Hospital of Shandong University, China (approval No. KYLL-2015(KS)-088) on February 10, 2015. |
| Databáze: | OpenAIRE |
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