Regulation of transferrin receptor expression and ferritin content in human mononuclear phagocytes. Coordinate upregulation by iron transferrin and downregulation by interferon gamma.

Abstract

We have investigated the regulation of key human iron binding proteins in mononuclear phagocytes by IFNy and iron transferrin. In a previous study, we demonstrated that IFN-y downregulates the expression on human monocytes of transferrin receptors, the major source of iron for the cell. In the present study, we show that IFNy also downregulates the intracellular concentration of ferritin, the major iron storage protein in the cell. By radioimmunoassay, the mean ferritin content of nonactivated monocytes was 361±107 fg/monocyte (mean±SEM) whereas the mean ferritin content of IFNy-activated monocytes was 64±13 fg/monocyte, an 82% reduction with activation (P < 0.01, t test). Consistent with its downregulating effect on these iron proteins, IFNy treatment also results in decreased iron incorporation. IFNy-activated monocytes incorporated 33% less iron from 59Fe-transferrin than nonactivated monocytes (P < 0.05, t test). Gel filtration chromatography revealed that incorporated iron is located primarily in ferritin in both nonactivated and IFN-y-activated monocytes. Ferritin in IFN'yactivated monocytes is saturated with approximately three times as much 59Fe as ferritin in nonactivated monocytes.We have also explored the effect of iron transferrin on transferrin receptor expression and intracellular ferritin content in human monocytes. We have found that iron transferrin markedly upregulates both transferrin receptor expression and intracellular ferritin content in both nonactivated (2.3-and 1.3-fold, respectively) and IFN'y-activated (3.4-and 2.9-fold, respectively) monocytes.This study demonstrates that transferrin receptor expression and intracellular ferritin content in human monocytes is unidirectionally and coordinately upregulated by iron transferrin and unidirectionally and coordinately downregulated by IFN-y. (J. Clin. Invest. 1993. 91:969-976.)

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

“…We demonstrated that, in vitro, activation by IL-4 elicits a host macrophage type that is less hostile to intracellular M. tuberculosis, due to several factors including transcriptional regulation of arginase 1/iNOS and TfR. IFN-c activation down-regulates TfR expression [81], resulting in decreased iron uptake by the host cell [82], and IL-4 antagonizes the inhibitory effect of IFN-c activation on TfR mRNA expression [47]. Here, we demonstrate that during M. tuberculosis infection alternatively activated macrophages strikingly differ from classically activated macrophages in their ability to down-regulate TfR expression and that iron availability to intracellular M. tuberculosis is increased by alternative activation, as shown by down-regulation of mycobactin synthesis and up-regulation of bacterioferritin transcripts.…”

Interferon-γ Listericidal Action Is Mediated by Novel Rab5a Functions at the Phagosomal Environment

“…At the molecular level, IFN-␥ signaling up-regulates the levels of endosomal/lysosomal proteins, such as cathepsin-D (21) and Rab5a (13), and down-regulates endosomal markers, such as the mannose and the transferrin receptors, TfR (22,23), while other Rabs remain unaffected (i.e. Rab5b, Rab5c, Rab7, or Rab11) (13).…”

Immune-mediated control of Chlamydia infection

“…Indoleamine 2,3-dioxygenase can inhibit Chlamydia growth by catalysing the catabolism of tryptophan, one of the amino acids that Chlamydia scavenges from the host cell. Lastly, IFN-g-mediated downregulation of the transferrin receptor may also limit Chlamydia growth by limiting the intracellular stores of iron available to the organism (Byrd and Horwitz, 1993;Freidank et al, 2001).…”