Interleukin-1beta increases binding of the iron regulatory protein and the synthesis of ferritin by increasing the labile iron pool.
This study was undertaken to begin to elucidate the mechanisms by which cytokines influence intracellular iron homeostasis. Intracellular iron homeostasis is maintained by the coordinated regulation of ferritin and transferrin receptor synthesis. The synthesis of these proteins is coordinated by cytoplasmic iron regulatory proteins (IRP), which bind to iron responsive elements (IRE) on their mRNAs. We evaluated the effects of interleukin-1beta (IL-1beta) on iron metabolism in human astrocytoma cells (SW1088). Exposure to IL-1beta for 16 h increased binding of the IRPs to the IRE and also increased ferritin synthesis. Using the iron sensitive dye calcein, we determined that the intracellular labile iron pool increased within 4 h of IL-1beta exposure and continued to increase for 8 h, returning to normal by 16 h. We propose that the cytokine induced increase in the labile iron pool stimulates ferritin synthesis resulting in a subsequent decrease in the labile iron pool. The decrease in the labile iron pool is consistent with the increase in IRE/IRP interaction measured at 16 h. These results indicate that cytokines can influence the labile iron pool and the post-transcriptional regulatory mechanism for maintaining iron homeostasis. These results contribute to understanding the response of ferritin to inflammation by suggesting ferritin synthesis may reflect changes in the labile iron pool. The approach used in this study may provide a model system for studying relations between the labile iron pool and proteins responsible for maintaining intracellular homeostasis
Piñero
D J
DJ
Department of Neuroscience and Anatomy, G.M. Leader Family Laboratory for Alzheimer's Disease Research, The Pennsylvania State University College of Medicine, M.S. Hershey Medical Center, Hershey, PA 17033, USA.
Hu
J
J
Cook
B M
BM
Scaduto
R C
RC
Connor
J R
JR
D000154:Aconitate Hydratase / Q000378:metabolism; D015153:Blotting, Western; D003593:Cytoplasm / Q000378:metabolism; D005293:Ferritins / Q000096:biosynthesis*; D005470:Fluorometry; D006706:Homeostasis; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007501:Iron / Q000032:analysis*; D007502:Iron Chelating Agents / Q000494:pharmacology; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D007375:Interleukin-1; D007502:Iron Chelating Agents; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D016601:RNA-Binding Proteins; D005293:Ferritins; D007501:Iron; D000154:Aconitate Hydratase