Preconditioning with cobalt chloride or desferrioxamine protects oligodendrocyte cell line (MO3.13) from tumor necrosis factor-alpha-mediated cell death.
Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor induced under hypoxic conditions. HIF-1alpha promotes the expression of genes encoding proteins that increase the cellular supply of oxygen and promote survival in periods of cellular stress and availability of cellular energy. We examined the effect of desferrioxamine (DFO) and cobalt chloride (CoCl(2)), two agents known to increase the stability of HIF-1alpha, and its effect on the survivability of an oligodendroglial cell line, MO3.13, when cultured with tumor necrosis factor-alpha (TNFalpha). Our studies showed that, unlike a murine microglial cell line (BV-2), MO3.13 cells do not induce HIF-1alpha in the presence of TNFalpha. MO3.13 cells do stabilize HIF-1alpha in the presence of DFO or CoCl(2). When MO3.13 cell were preconditioned with either DFO or CoCl(2), addition of TNFalpha further increased protein levels of HIF-1alpha. The mechanisms that underlie the increase in protein levels of HIF -1alpha seen, following addition of TNFalpha in preconditioned cells is due to an increase in transcription of the HIF-1alpha gene. Increased cellular levels of HIF-1alpha is associated with improved survival of MO3.13 cells, when cultured with TNFalpha after a period of preconditioning by DFO or CoCl(2). These studies suggest that compoundsthat increase HIF-1alpha can function as neuroprotective agents in inflammatory disorders of the CNS.
Yao
Song-yi
SY
Department of Neurology, Multiple Sclerosis Research Center, Vanderbilt University Medical Center, Nashville, Tennessee 37212, USA.
Soutto
Mohammed
M
Sriram
Subramaniam
S
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002460:Cell Line; D003035:Cobalt / Q000494:pharmacology*; D003676:Deferoxamine / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism; D008856:Microscopy, Fluorescence; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D003035:Cobalt; C018021:cobaltous chloride; D003676:Deferoxamine