Regulation of iron metabolism in the acute-phase response: interferon gamma and tumour necrosis factor alpha induce hypoferraemia, 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), recombinant human interferon gamma (rIFN-gamma) and melphalan on interleukin (IL) 6 and acute-phase protein levels, iron status and serum transferrin receptor (sTfR) levels in 12 patients with melanoma or sarcoma. Patients were treated with ILP during 90 min after pretreatment with rIFN-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 maximum levels at 4h. C-reactive protein (CRP) rose at 4 h 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 decreased after ILP and recovered after day 2. Serum iron and sTfR levels decreased during pretreatment and after ILP to minimum levels at 8 h and day 1 respectively. This was associated with an increase in serum ferritin levels, which paralleled CRP values.


CONCLUSIONS
Our data point to a central role for the cytokine network in the modulation of iron metabolism in the acute-phase response and anaemia of chronic disease. TNF, possibly via induction of IL-6, and IFN-gamma induce hypoferraemia, which may in part result from a decrease in tissue iron release based on a primary stimulation of ferritin synthesis. The fall in sTfR levels may reflect an impaired erythroid growth and/or TfR expression mediated by TNF and IFN-gamma.
Feelders
R A
RA
Erasmus University, Rotterdam, The Netherlands.
Vreugdenhil
G
G
Eggermont
A M
AM
Kuiper-Kramer
P A
PA
van Eijk
H G
HG
Swaak
A J
AJ
D000209:Acute-Phase Proteins / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000740:Anemia / Q000097:blood / Q000209:etiology / Q000628:therapy*; D002097:C-Reactive Protein / Q000378:metabolism; D010478:Chemotherapy, Cancer, Regional Perfusion; D005260:Female; D005293:Ferritins / Q000096:biosynthesis* / Q000097:blood; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000097:blood; D007501:Iron / Q000097:blood / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000097:blood* / Q000150:complications / Q000473:pathology / Q000628:therapy; D008558:Melphalan / Q000627:therapeutic use; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009961:Orosomucoid / Q000378:metabolism; D011990:Receptors, Transferrin / Q000097:blood*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012509:Sarcoma / Q000097:blood* / Q000150:complications / Q000628:therapy; D012709:Serum Albumin / Q000378:metabolism; D013997:Time Factors; D014168:Transferrin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D000515:alpha 1-Antitrypsin / Q000378:metabolism
D000209:Acute-Phase Proteins; D015850:Interleukin-6; D009961:Orosomucoid; D011990:Receptors, Transferrin; D011994:Recombinant Proteins; D012709:Serum Albumin; D014168:Transferrin; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D007371:Interferon-gamma; D002097:C-Reactive Protein; D005293:Ferritins; D007501:Iron; D008558:Melphalan