Polychlorinated biphenyls induce proinflammatory cytokine release and dopaminergic dysfunction: protection in interleukin-6 knockout mice.
Proinflammatory cytokines are not only important mediators of brain development, but also pose an increased risk for neurodegeneration following exposure to neurotoxicants or trauma. We have used the ubiquitous environmental and occupational neurotoxicant polychlorinated biphenyls (PCBs) to investigate the putative role of inflammatory agents in mediating processes involved in basal ganglia dysfunctions. PCBs induced inflammatory responses in C57BL/6 adult male mice, significantly elevating serum levels of IL-6 (31%), IL-1beta (71%) and TNF-alpha (22%) and significantly reducing striatal dopamine (DA, 21%), tyrosine hydroxylase (TH, 26%), dopamine transporter (DAT, 39%), and synaptophysin (29%) concentrations. We also exposed mice deficient in the proinflammatory cytokine interleukin-6 (IL-6-/-) to PCBs, to explore the role of this specific cytokine in mediating PCB-induced DA neurodegeneration. Not only did the PCB-treated IL-6-/- mice exhibit a decrease in serum levels of IL-1beta and TNF-alpha, but they were also protected from PCB-induced striatal dopaminergic dysfunction, displaying no signs of toxicant-induced reductions in DA levels, or TH, DAT or synaptophysin expression. Taken together, these results suggest that: (1) PCB exposure results in a peripheral inflammatory response associated with striatal terminal degeneration; and (2) the absence of IL-6 prevents PCB-induced dopaminergic losses in the striatum.
Goodwill
Meleik Hebert
MH
Wadsworth Center, New York State Department of Health, Albany, NY 12201, United States. goodwill@wadsworth.org
Lawrence
David A
DA
Seegal
Richard F
RF
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004785:Environmental Pollutants / Q000494:pharmacology*; D015850:Interleukin-6 / Q000172:deficiency*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D016708:Synaptophysin / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D016207:Cytokines; D004785:Environmental Pollutants; D015850:Interleukin-6; D016708:Synaptophysin; D011078:Polychlorinated Biphenyls; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine