title: Regulation of ubiquitin-specific processing protease 8 suppresses neuroinflammation.
abstract: In our previous study, we reported that luteolin might exert neuroprotective functions by inhibiting the production of proinflammatory mediators, thereby suppressing microglial activation. In this study, we used two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS) to study the effect of ubiquitin-specific processing protease 8 (USP8) in luteolin-treated microglia. Western blot analysis verified that USP8 expression is upregulated by luteolin. Researchers have found that USP8 markedly enhanced the stability of neuregulin receptor degradation protein-1 (Nrdp1), which in turn inhibited the production of proinflammatory cytokines in toll-like receptor-triggered macrophages. We next hypothesized that luteolin inhibits microglial inflammation by regulating USP8 gene expression. After transfecting BV2-immortalized murine microglial cells with USP8, a significant reduction in the degradation of Nrdp1 was observed. USP8 overexpression also reduced the production of lipopolysaccharide (LPS)-induced proinflammatory mediators such as inducible nitric oxide synthase (iNOS), nitric oxide (NO), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2). We also found that USP8 siRNA blocked luteolin inhibition of pro-inflammatory gene expression such as iNOS, NO, COX-2, and PGE2. Taken together, our findings suggested that luteolin inhibits microglial inflammation by enhancing USP8 protein production. We concluded that in addition to anti-inflammatory luteolin, USP8 might represent a novel mechanism for the treatment of neuroinflammation and neurodegeneration.
authors.affiliation: Department of Pathophysiology, Institute of Brain Research, School of Medicine, JiNan University, Guangzhou 510632, PR China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Neurology, First Affiliated Hospital of JiNan University, Guangzhou 510630, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Bi
authors.affiliation: Department of Pathophysiology, Institute of Brain Research, School of Medicine, JiNan University, Guangzhou 510632, PR China.
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.affiliation: Department of Pathophysiology, Institute of Brain Research, School of Medicine, JiNan University, Guangzhou 510632, PR China.
authors.forename: Chanjuan
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Institute of Brain Research, School of Medicine, JiNan University, Guangzhou 510632, PR China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Shu
authors.affiliation: Department of Pathophysiology, Institute of Brain Research, School of Medicine, JiNan University, Guangzhou 510632, PR China.
authors.forename: Huadong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Institute of Brain Research, School of Medicine, JiNan University, Guangzhou 510632, PR China.
authors.forename: Renbing
authors.initials: R
authors.lastname: Qi
authors.affiliation: Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94304, USA.
authors.forename: Qiaoyun
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Pathophysiology, Institute of Brain Research, School of Medicine, JiNan University, Guangzhou 510632, PR China. Electronic address: ldx_jnu@sina.com.
authors.forename: Daxiang
authors.initials: D
authors.lastname: Lu
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D047311:Luteolin / Q000494:pharmacology; D051379:Mice; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C435904:Rnf41 protein, mouse; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; C541536:Usp8 protein, mouse; D015232:Dinoprostone; D047311:Luteolin
keywords: Luteolin; Microglia; Neuroinflammation; Neuroprotection; Nrdp 1; USP 8