Role of HIF-1 and NF-kappaB transcription factors in the modulation of transferrin receptor by inflammatory and anti-inflammatory signals.
Inflammation generates various changes in body iron homeostasis, including iron sequestration in the reticuloendothelial system with ensuing hypoferremia and anemia of chronic disease. Increased iron accumulation is caused by hepcidin-mediated down-regulation of the iron export protein ferroportin and higher iron uptake. However, enhanced iron acquisition by macrophages cannot be accounted for by the previously reported transferrin receptor (TfR1) down-regulation in macrophages exposed to lipopolysaccharide (LPS)/interferon gamma (IFNgamma) because it impairs a major iron uptake mechanism. Because TfR1 is up-regulated by the hypoxia-inducible factor (HIF-1), we investigated the effect of inflammatory and anti-inflammatory signals on HIF-1-mediated TfR1 gene expression. Exposure of mouse macrophages (RAW 264.7 and J774A.1 cells or peritoneal macrophages) to LPS/IFNgamma up-regulated NF-kappaB, which in turn rapidly and transiently activated HIF-1-dependent TfR1 expression and iron uptake. Activation of an anti-inflammatory pathway by pre-exposure to the adenosine A(2A) receptor agonist CGS21680 prevented the inducing effect of LPS/IFNgamma on HIF-1 and TfR1 expression by inhibiting NF-kappaB activity, whereas treatment with CGS21680 alone increased HIF-1-mediated TfR1 expression by means of an NF-kappaB-independent signaling pathway. In conclusion, an interplay of the HIF-1 and NF-kappaB pathways controls TfR1 transcription in inflammation. The consequent changes in TfR1 expression may be involved in modulating iron retention in inflammatory macrophages, thus possibly contributing to the development of hypoferremia in the early phases preceding the down-regulation of macrophage ferroportin by hepcidin.
Institute of General Pathology, University of Milan, Via Mangiagalli 31, 20133 Milan, Italy.
Lorenza
L
Tacchini
Elena
E
Gammella
Cristina
C
De Ponti
Stefania
S
Recalcati
Gaetano
G
Cairo
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism / Q000502:physiology*; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D043683:Receptors, Adenosine A2 / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism*; D013997:Time Factors
D000893:Anti-Inflammatory Agents; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; D016328:NF-kappa B; D043683:Receptors, Adenosine A2; D011990:Receptors, Transferrin; D007371:Interferon-gamma; D007501:Iron