REGULATION OF IRON-METABOLISM IN THE ACUTE-PHASE RESPONSE - INTERFERON-GAMMA AND TUMOR-NECROSIS-FACTOR-ALPHA INDUCE HYPOFERREMIA, FERRITIN PRODUCTION AND A DECREASE IN CIRCULATING TRANSFERRIN RECEPTORS IN CANCER-PATIENTS

Background The acute-phase response and anaemia of chronic disease are characterized by hypoferraemia associated with an increased ferritin synthesis, which might be mediated by the activated cytokine cascade. Methods We examined the prolonged effects of isolated limb perfusion ( ILP) with recombinant human tumour necrosis factor alpha (rTNF), recom binant human interferon gamma (rIFN-gamma) and melphalan on interleuki n (IL) 6 and acute-phase protein levels, iron status and serum transfe rrin receptor (sTfR) levels in 12 patients with melanoma or sarcoma. P atients were treated with ILP during 90 min after pretreatment with rI FN-gamma during 2 days. Results After ILP, leakage of TNF resulted in systemic peak levels at 3 min followed by an increase in IL-6 with max imum levels at 4h. C-reactive protein (CRP) rose at 4h to peak levels at day 2, whereas alpha(1)-antitrypsin and alpha(1)-acid glycoprotein increased to maximum levels at day 3. Albumin and transferrin levels d ecreased after ILP and recovered after day 2. Serum iron and sTfR leve ls decreased during pretreatment and after ILP to minimum levels at 8 h and day 1 respectively. This was associated with an increase in seru m ferritin levels, which paralleled CRP values. Conclusions Our data p oint to a central role for the cytokine network in the modulation of i ron metabolism in the acute-phase response and anaemia of chronic dise ase. TNF, possibly via induction of n-6, and IFN-gamma induce hypoferr aemia, which may in part result from a decrease in tissue iron release based on a primary stimulation of ferritin synthesis. The fall in sTf R levels may reflect an impaired erythroid growth and/or TfR expressio n mediated by TNF and IFN gamma.