Blood Cells - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 82

iron and transferrin. Transferrin receptor-1 is expressed on all dividing cells. 47
Erythrocyte precursors bind transferrin to incorporate iron into heme. Transferrin
receptor-2 is expressed mainly in the liver and binds transferrin-iron complex with
a much lower affinity than that of transferrin receptor-1.
Cellular iron is used or stored by ferritin . 48 According to iron status, con-
centrations in iron transporters, carriers, and storage proteins, it is regulated
transcriptionally by cytokines and post-transcriptionally owing to iron-regulatory
proteins IRP1 and IRP2.
Ferritin is an intra- and extracellular protein. Plasma ferritin has a low iron
content and distinct subunit composition. Ferritin binds high-molecular-weight
kininogen to inhibit its cleavage by kallikrein, hence reducing production of
bradykinin and cleaved high-molecular-weight kininogen. In addition, ferritin and
high-molecular-weight kininogen colocalize in inflammation sites, 49 where ferritin
inhibits the cleavage of high-molecular-weight kininogen by tryptase and elastase.
In addition, plasma light (L) and heavy (H) chain-enriched ferritin preferentially
bind to plasmalemmal scavenger receptor ScaRa5 and T-cell immunoglobulin and
mucin domain-containing protein TIMD2 that trigger endocytosis of the receptor-
ferritin pair [ 152 ].
Small peptidic hormone hepcidin is a regulator of iron metabolism and systemic
homeostasis to avoid pathological conditions of deficiency or overload. Hepcidin
controls the surface expression of iron exporter ferroportin (Fpn or SLC40a1) on
the basolateral membrane of duodenal enterocytes and on iron-recycling macro-
phages that process senescent erythrocytes. Interaction of hepcidin with ferroportin
precludes iron export from duodenal enterocytes and macrophages. Hepcidin is
secreted by the liver 50 to adapt iron absorption to the body's need. Hepcidin
transcription is controlled by iron and oxygen sensors, as well as inflammation.
Hepcidin level increases with iron overload. Conversely, hepcidin expression is
suppressed when iron is required for erythropoiesis. In addition, hepcidin is
upregulated by inflammatory cytokines. Circulating hepcidin binds to ferroportin
for degradation, and hence inhibits iron export into plasma.
Hepcidin expression depends on bone morphogenetic proteins (BMP2, BMP4,
andBMP9invitro)andtheSMAD4pathway 51 On the hepatocyte surface,

47 Transferrin receptor-1 is a transmembrane homodimer. The extracellular domain binds one trans-
ferrin per subunit. Transferrin-iron complex is then rapidly internalized via clathrin-coated pits into
endosome acidified by ATP-dependent proton pump. Acidification releases iron. Endosomal Fe 3 +
is converted into Fe 2 + by STEAP3 ferrireductase.
48 Ferritin is a multimer of 24 subunits that include subunit-H (for heavy or heart) and -L (for light
and liver). Ferritin subunits form a central core that contains up to 4,500 atoms of iron. Monomeric
H-ferritin has ferroxidase activity that converts stored Fe 2 + into Fe 3 + .
49 Monomeric H-ferritin is upregulated by cytokines such as TNF α .
50 Hepcidin mRNA that is generated from gene HAMP (hepcidin antimicrobial peptide) is also
detected in heart, pancreas, and hematopoietic cells.
51 When BMP ligands bind and activate receptor Ser/Thr kinases on hepatocyte surface, these BMP
receptors phosphorylate cytoplasmic effectors SMAD1, SMAD5, and SMAD8 that then form a