Acute Phase Proteins: Ferritin and Ferritin Isoforms

Ferritin is a positive acute phase reactant, exhibiting increased levels in blood during the acute phase response. Nevertheless, the precise role of ferritin as an acute phase reactant remains to be clarified. As for other acute phase proteins, ferritin is produced and secreted by hepatocytes. However, ferritin is also produced and secreted by other cell types, including macrophages and cancer cells. Many isoforms of ferritin (isoferritins) are found in the body, depending on the H-subunit to L-subunit ratio in the ferritin protein shell. The subunit composition of ferritin molecules is a major determinant of the functional properties of the ferritin isoforms. Expression of ferritin and its subunits is governed by the amount of metabolically available iron, the presence of oxidative stress and both proand antiinflammatory cytokines. Ferritin as an acute phase reactant is well known for its intracellular iron sequestration and storage abilities during immune activation (Weiss & Goodnough, 2005). This function is of high importance for protection of the body against microbial proliferation, oxidative damage, inflammation and cancer. Although the regulation of iron appears to be a primary function of ferritin in both normal conditions and during the acute phase response, other functions, beyond the control of iron bio-availability, have also been described. Although more investigations are required in order to clarify the precise role of ferritin as an acute phase reactant, this chapter shows a synopsis on the present knowledge on ferritin during the acute phase response. In the first part of this chapter (2-4), the processes of iron sequestration, storage and release by the ferritin molecule, the significance of the presence of isoferritins, and the regulation of the expression of ferritin by iron are described. In the next section (5) changes with diseases, and possible significance of extracellular (plasma) ferritin is discussed. In the last section (6-11) the differential up-regulation of H-subunit rich ferritins during the acute phase response, the importance of H-subunit rich ferritins in the withholding of iron by the macrophage, as well as its role in immune modulation, its pro-apoptotic and anti-apoptotic activities, and variations in cancer are addressed.