title: Globular adiponectin induces a pro-inflammatory response in human astrocytic cells.
abstract: Neuroinflammation, mediated in part by activated brain astrocytes, plays a critical role in the development of neurodegenerative disorders, including Alzheimer's disease (AD). Adiponectin is the most abundant adipokine secreted from adipose tissue and has been reported to exert both anti- and pro-inflammatory effects in peripheral tissues; however, the effects of adiponectin on astrocytes remain unknown. Shifts in peripheral concentrations of adipokines, including adiponectin, could contribute to the observed link between midlife adiposity and increased AD risk. The aim of the present study was to characterize the effects of globular adiponectin (gAd) on pro-inflammatory cytokine mRNA expression and secretion in human U373 MG astrocytic cells and to explore the potential involvement of nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and phosphatidylinositide 3-kinases (PI3K) signaling pathways in these processes. We demonstrated expression of adiponectin receptor 1 (adipoR1) and adipoR2 in U373 MG cells and primary human astrocytes. gAd induced secretion of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1, and gene expression of IL-6, MCP-1, IL-1β and IL-8 in U373 MG cells. Using specific inhibitors, we found that NF-κB, p38MAPK and ERK1/2 pathways are involved in gAd-induced induction of cytokines with ERK1/2 contributing the most. These findings provide evidence that gAd may induce a pro-inflammatory phenotype in human astrocytes.
authors.affiliation: School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC, Canada.
authors.forename: Zhongxiao
authors.initials: Z
authors.lastname: Wan
authors.affiliation: School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC, Canada.
authors.forename: Dorrian
authors.initials: D
authors.lastname: Mah
authors.affiliation: School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC, Canada.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Simtchouk
authors.affiliation: Department of Biology, University of British Columbia Okanagan, Kelowna, BC, Canada.
authors.forename: Andis
authors.initials: A
authors.lastname: Klegeris
authors.affiliation: School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC, Canada. Electronic address: jonathan.little@ubc.ca.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Little
mesh_terms: D052242:Adiponectin / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054419:Receptors, Adiponectin / Q000378:metabolism
chemical_list: C499918:ADIPOQ protein, human; C475418:ADIPOR1 protein, human; C475420:ADIPOR2 protein, human; D052242:Adiponectin; C111835:CCL2 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; D005419:Flavonoids; C508600:IL6 protein, human; D007093:Imidazoles; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D011725:Pyridines; D012333:RNA, Messenger; D054419:Receptors, Adiponectin; D019869:Phosphatidylinositol 3-Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Astrocytes; Extracellular signal-regulated kinase (ERK) 1/2; Globular adiponectin; Neuroinflammation