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Department of Internal Medicine, University of Innsbruck, Innsbruck, Austria
We have previously shown that iron regulates the transcription of
inducible nitric oxide synthase (iNOS). To elucidate the underlying
mechanisms we performed a series of transient transfections of murine
fibroblast (NIH-3T3) and macrophage-like cells (J774.A1) with reporter
plasmids containing the iNOS promoter and deletions thereof. By means
of this and subsequent DNase I footprinting analysis we identified a
regulatory region between -153 and -142 bp upstream of the
transcriptional start site of the iNOS promoter that was sensitive to
regulation by iron perturbation. Gel shift and supershift assays
revealed that the responsible protein for this observation is NF-IL6, a
member of the CCAAT/enhancer binding protein family of transcription
factors. Binding of NF-IL6 to its consensus motif within the iNOS
promoter was inducible by IFN-
and/or LPS, was reduced by iron, and
was enhanced by the iron chelator desferrioxamine. Introduction of a
double mutation into the NF-IL6 binding site (-153/-142) of an iNOS
promoter construct resulted in a reduction of IFN-/LPS inducibility
by >90% and also impaired iron mediated regulation of the iNOS
promoter. Our results provide evidence that this NF-IL6 binding site is
of central importance for maintaining a high transcriptional rate of
the iNOS gene after IFN-/LPS stimulation, and that NF-IL6 may
cooperate with hypoxia inducible factor-1 in the orchestration of
iron-mediated regulation of iNOS.
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