Cytokine toxicity to oligodendrocyte precursors is mediated by iron.

Glia. 2005 Jun 20;
Zhang X, Haaf M, Todorich B, Grosstephan E, Schieremberg H, Surguladze
N,
Connor JR

Inflammatory processes play a key role in the pathogenesis of a number
of
common neurodegenerative disorders such as Alzheimer's disease (AD),
Parkinson's disease (PD), and multiple sclerosis (MS). Abnormal iron
accumulation is frequently noted in these diseases and compelling
evidence
exists that iron is involved in inflammatory reactions. Histochemical
stains
for iron repeatedly demonstrate that oligodendrocytes, under normal
conditions, stain more prominently than any other cell type in the
brain.
Therefore, we examined the hypothesis that cytokine toxicity to
oligodendrocytes is iron mediated. Oligodendrocytes in culture were
exposed
to interferon-gamma (IFN-gamma), interleukin-1beta (IL-1beta), and
tumor
necrosis factor-alpha (TNF-alpha). Toxicity was observed in a
dose-dependent
manner for IFN-gamma and TNF-alpha. IL-1beta was not toxic in the
concentrations used in this study. The toxic concentration of
IFN-gamma, and
TNF-alpha was lower if the cells were iron loaded, but iron loading had
no
effect on the toxicity of IL-1beta. These data provide insight into the
controversy regarding the toxicity of cytokines to oligodendrocytes by
revealing that iron status of these cells will significantly impact the
outcome of cytokine treatment. The exposure of oligodendrocytes to
cytokines
plus iron decreased mitochondrial membrane potential but activation of
caspase 3 is limited. The antioxidant, TPPB, which targets
mitochondria,
protected the oligodendrocytes from the iron-mediated cytotoxicity,
providing further support that mitochondrial dysfunction may underlie
the
iron-mediated cytokine toxicity. Therapeutic strategies involving
anti-inflammatory agents have met with limited success in the treatment
of
demyelinating disorders. A better understanding of these agents and the
contribution of cellular iron status to cytokine toxicity may help
develop a
more consistent intervention strategy. (c) 2005 Wiley-Liss, Inc.

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