Central role of transcription factor NF‐IL6 for cytokine and iron‐mediated regulation of murine inducible nitric oxide synthase expression

Iron chelators antagonize a direct inhibitory effect of iron toward the expression of iNOS.

“Thereby iron chelators antagonize a direct inhibitory effect of iron toward the expression of iNOS (Weiss et al., 1994; Melillo et al., 1997; Dlaska and Weiss, 1999).”

Negative effects of iron on NOS2 transcription can be referred to reduced binding affinity of transcription factors NF-IL6 and HIF-1 to the NOS2 promoter.

“The negative effects of iron on NOS2 transcription, which can be referred to a reduced binding affinity of the transcription factors NF-IL6 (C/EBP-β) and hypoxia inducible factor 1 (HIF-1) to the NOS2 promoter (167, 189, 191), is part of a regulatory feedback loop, by which NO modulates the IRE-binding function of IRPs, thereby affecting ferritin translation and intracellular iron availability and”

Macrophage functions driven by IFN-γ are impaired when macrophages are exposed to surplus iron largely because iron directly inhibits the binding activities of NF-IL6 and HIF-1α.

“Specifically, macrophage functions driven by IFN-γ are impaired when macrophages are exposed to surplus iron [138, 162, 176] largely because iron directly inhibits the binding activities of the transcription factors nuclear factor interleukin-6 (NF-IL6) and hypoxia-inducible factor (HIF)-1α [55, 153] [176].”

Intracellular iron accumulation in macrophages represses IFNγ receptor signaling, most likely explaining why reducing intracellular iron content promotes IFNγ-driven resistance pathways involving MHC class II, iNOS/NOS2, TNF, IL-6, or IL-12 expression.

“Intracellular Fe accumulation in Mø represses IFNc receptor signaling, most likely explaining why reducing intracellular Fe content promotes IFNc-driven resistance pathways involving the induction of histocompatibility (MHC) class II, iNOS/NOS2 TNF, IL-6, or IL-12 expression [164][165][166][167].”