期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 285, 期 53, 页码 41921-41934出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.164020
关键词
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资金
- Fundacao para a Ciencia e a Tecnologia Portugal
- Fundo-Europeu-De-Desenvolvimento-Regional Grants [PTDC/SAU-NEU/68465/2006, PTDC/SAU-OSM/101469/2008, SFRH/BD/23595/2005]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/23595/2005, PTDC/SAU-NEU/68465/2006, PTDC/SAU-OSM/101469/2008] Funding Source: FCT
Given the modulatory role of neuropeptide Y (NPY) in the immune system, we investigated the effect of NPY on the production of NO and IL-1 beta in microglia. Upon LPS stimulation, NPY treatment inhibited NO production as well as the expression of inducible nitric-oxide synthase (iNOS). Pharmacological studies with a selective Y-1 receptor agonist and selective antagonists for Y-1, Y-2, and Y-5 receptors demonstrated that inhibition of NO production and iNOS expression was mediated exclusively through Y-1 receptor activation. Microglial cells stimulated with LPS and ATP responded with a massive release of IL-1 beta, as measured by ELISA. NPY inhibited this effect, suggesting that it can strongly impair the release of IL-1 beta. Furthermore, we observed that IL-1 beta stimulation induced NO production and that the use of a selective IL-1 receptor antagonist prevented NO production upon LPS stimulation. Moreover, NPY acting through Y1 receptor inhibited LPS-stimulated release of IL-1 beta, inhibiting NO synthesis. IL-1 beta activation of NF-kappa B was inhibited by NPY treatment, as observed by confocal microscopy and Western blotting analysis of nuclear translocation of NF-kappa B p65 subunit, leading to the decrease of NO synthesis. Our results showed that upon LPS challenge, microglial cells release IL-1 beta, promoting the production of NO through a NF-kappa B-dependent pathway. Also, NPY was able to strongly inhibit NO synthesis through Y1 receptor activation, which prevents IL-1 beta release and thus inhibits nuclear translocation of NF-kappa B. The role of NPY in key inflammatory events may contribute to unravel novel gateways to modulate inflammation associated with brain pathology.
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