Manganese modulates pro-inflammatory gene expression in activated glia.
Redox-active metals are of paramount importance for biological functions. Their impact and cellular activities participate in the physiological and pathophysiological processes of the central nervous system (CNS), including inflammatory responses. Manganese is an essential trace element and it is required for normal biological activities and ubiquitous enzymatic reactions. However, excessive chronic exposure to manganese results in neurobehavioral deficits. Recent evidence suggests that manganese neurotoxicity involves activation of microglia or astrocytes, representative CNS immune cells. In this study, we assessed the molecular basis of the effects of manganese on the modulation of pro-inflammatory cytokines and nitric oxide (NO) production in primary rat cortical glial cells. Cultured glial cells consisted of 85% of astrocytes and 15% of microglia. Within the assayed concentrations, manganese was unable to induce tumor necrosis factor alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) expression, whereas it potentiated iNOS and TNF-alpha gene expression by lipopolysaccharide/interferon-gamma-activated glial cells. The enhancement was accompanied by elevation of free manganese, generation of oxidative stress, activation of mitogen-activated protein kinases, and increased NF-kappaB and AP-1 binding activities. The potentiated degradation of inhibitory molecule IkappaB-alpha was one of underlying mechanisms for the increased activation of NF-kappaB by manganese. However, manganese decreased iNOS enzymatic activity possibly through the depletion of cofactor since exogenous tetrahydrobiopterin reversed manganese's action. These data indicate that manganese could modulate glial inflammation through variable strategies.
Chen
Chun-Jung
CJ
Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan. cjchen@vghtc.gov.tw
Ou
Yen-Chuan
YC
Lin
Shih-Yi
SY
Liao
Su-Lan
SL
Chen
Shih-Yun
SY
Chen
Jian-Hong
JH
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D004660:Encephalitis / Q000139:chemically induced* / Q000235:genetics* / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005911:Gliosis / Q000139:chemically induced* / Q000235:genetics* / Q000503:physiopathology; D020672:I-kappa B Proteins / Q000378:metabolism; D008345:Manganese / Q000633:toxicity*; D020149:Manganese Poisoning / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D001708:Biopterins; D009569:Nitric Oxide; D008345:Manganese; D052247:Nitric Oxide Synthase Type II; C003402:sapropterin