Modulation of cell proliferation and cytokine production in AML by recombinant interleukin-1 receptor antagonist.
In Acute Myelogenous Leukemia (AML), Interleukin 1 (IL-1) might sustain autocrine and paracrine loops of leukemic growth. An IL-1 inhibitor has been recently purified and cloned. This molecule binds to the IL-1 receptors but has no IL-1 like activity fulfilling the characteristics of a pure Interleukin-1 receptor antagonist (IL-1ra). We studied the in vitro effect of human recombinant IL-1ra on proliferation of AML blasts. Spontaneous as well as IL-1 stimulated AML proliferation was significantly inhibited by the addition of 50 ng/ml of recombinant IL-1ra in a dose dependent manner. The inhibitory effect of IL-1ra was measurable after 12 hours of culture and reached a plateau at 60 hrs. We found that IL-1ra could compete with IL-1 in binding to specific IL-1 receptors on AML cells. As expected, culture supernatants of unstimulated leukemic samples contained IL-1 beta and GM-CSF activity. The incubation of the same leukemic blasts with IL-1 ra was followed by reduction or disappearance of GM-CSF in culture supernatants whereas the IL-1 beta production was only partially modulated. By Northern blot experiments performed on freshly isolated, uncultured leukemic blasts, we found a constitutive expression of the IL-1 beta gene in 19 of 23 AML cases analyzed. On the contrary, only three of these patients express the IL-1 RA mRNA. All together these results suggest that imbalanced secretion of IL-1 and its natural receptor antagonist could contribute to the unrestricted growth of AML cells.
Rambaldi
A
A
Division of Hematology, Ospedali Riuniti di Bergamo.
Torcia
M
M
Dinarello
C A
CA
Barbui
T
T
Cozzolino
F
F
D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012795:Sialoglycoproteins / Q000235:genetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D016207:Cytokines; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D012795:Sialoglycoproteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor