Reactive oxygen species mediate chloroquine-induced expression of chemokines by human astroglial cells.
We have previously demonstrated that chloroquine may evoke inflammatory responses in the central nervous system by inducing expression of pro-inflammatory cytokines by astroglial cells. In this study, we further examined the molecular mechanism responsible for chloroquine-induced activation of NF-kappaB and subsequent expression of chemokines by astroglial cells. We observed that (1) chloroquine induced expression of chemokines such as CCL2 and CXCL8 in a dose- and time-dependent manner in human astroglial cells; (2) other lysosomotropic agents such as ammonium chloride and bafilomycin A1 had minimal effects on chemokine expression; (3) inhibition of NF-kappaB by MG-132 and TPCK suppressed chloroquine-induced mRNA expression of chemokines; (4) chloroquine increased the intracellular level of reactive oxygen species (ROS) in a dose- and time-dependent manner by human astroglial cells, but not by monocytic/microglial cells; (5) chloroquine-induced increase of intracellular ROS level was suppressed by pre-incubation with diphenyl iodonium (DPI) and N-acetyl cysteine (NAC); and (6) inhibition of chloroquine-induced ROS production by DPI or NAC suppressed chloroquine-mediated activation of NF-kappaB and subsequent mRNA expression of chemokines in astroglial cells. These results collectively suggest that chloroquine generates ROS, which is responsible for NF-kappaB activation and subsequent expression of pro-inflammatory chemokines in human astroglial cells.
Park
Jinseu
J
Department of Genetic Engineering, College of Natural Science, Hallym University, Chunchon, Korea.
Choi
Kyungsun
K
Jeong
Eunjoo
E
Kwon
Daeho
D
Benveniste
Etty N
EN
Choi
Chulhee
C
D000111:Acetylcysteine / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D002738:Chloroquine / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology
D001713:Biphenyl Compounds; D018925:Chemokines; D018836:Inflammation Mediators; D007976:Leupeptins; D016328:NF-kappa B; D009861:Onium Compounds; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C031291:diphenyliodonium; D014108:Tosylphenylalanyl Chloromethyl Ketone; D002738:Chloroquine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine