Modulation of cell proliferation and cytokine production in acute myeloblastic leukemia by interleukin-1 receptor antagonist and lack of its expression by leukemic cells

Abstract

Interleukin-1 (IL-1) is spontaneously produced by acute myeloblastic leukemia (AML) cells. IL-1 also induces synthesis of colony-stimulating factors (CSFs) and sustains leukemic growth. An IL-1-specific inhibitor has been recently purified and cloned; this molecule binds to IL-1 receptors but has no IL-1 activity, fulfilling the characteristics of an IL-1 receptor antagonist (IL-1ra). Because high-affinity binding sites for IL-1ra were shown on AML cells by radioligand binding studies, we studied the effect of IL-1ra on the proliferative activity of blast cells isolated from 16 cases of AML. In each case, spontaneous proliferation was inhibited by addition of the IL-1ra in a dose- dependent manner (1 to 100 ng/mL). Culture supernatants of unstimulated leukemic cells contained IL-1 beta and granulocyte-macrophage CSF (GM- CSF), but when incubated with the IL-1ra, a reduction or disappearance of GM-CSF was observed in 8 of 10 cases, whereas spontaneous IL-1 production was reduced in four of seven cases. By Northern hybridization, IL-1 beta gene transcripts were shown in 20 of 23 AML cases, whereas IL-1ra-specific messenger RNA was present in only two of the patients studied. These data show a role for IL-1 in the spontaneous proliferation and cytokine production of AML cells and suggest that an imbalanced synthesis of IL-1 and of its natural receptor antagonist may contribute to the unrestricted growth of AML cells.

Intra‐tumoral interleukin‐6 down‐regulation system and genetic mutations of tumor suppressor genes in colorectal carcinoma

“…A decreased tumor tissue IL‐1ra/IL‐1 ratio has been shown in patients with head and neck squamous cell carcinomas 1. An imbalanced synthesis of IL‐1 and its natural receptor antagonist in leukemia cells was associated with unrestricted growth 21. Interleukin‐1ra‐positive mouse hepatic adenomas contained more proliferating cell nuclear antigen‐positive cells than IL‐1ra‐negative adenomas, indicating a link to high proliferation activity, although this was no longer evident in mouse hepatic carcinomas 22.…”

Interleukin‐1, Tumour Necrosis Factor and Treatment of the Septic Shock Syndrome

“…In vitro, the IL-lra appears to occupy the IL-lRtl on T cells and fibroblasts with nearly the same affinity as that for bone fide IL-l but without demonstrable agonist activity (69). Human IL-lra also blocks the binding of IL-l to human cells bearing IL-lRtll such as neutrophils and B cells (73) as well as human peripheral myelomonocytic leukemia cells (74). Using murine T cells (IL-lRtl), human IL-lra blocks the binding of IL-l at nearly equimolar concentration; however, a 10-to 50fold molar excess of IL-l ra is required to block the binding of human IL-I to human type II receptor bearing cells (73).…”

“…Antibodies to human IL-l~ reduce the spontaneous proliferation and colony stimulating activity production of juveniletype chronic granulocytic (80) and acute myelogenous leukemia cells (81). Recent studies have shown that IL-lra blocks the spontaneous proliferation as well as spontaneous production of GM-CSF, IL-l and IL-6 in peripheral blood-or bone marrow-derived acute myelogenous leukemia cells from over 25 patients (74). When IL-lra was removed after a 48 h exposure, the leukemic cells showed evidence of death during a subsequent 72 h incubation.…”

Interleukin‐1β stimulation of 45 Ca2+ release from rat striatal slices

“…injection of IL-I (Coceani et al, 1992). Finally, IRAP at a concentration two order of magnitudes higher than that of the IL-I, blocks IL-I binding to type I and type II receptors in different cultured cells (Rambaldi et al, 1990;Hannum et al, 1990;Dripps et al, 1991). The specificity of the IL-I action on Ca2" release is further outlined by the fact that levels of other cations (Na+, K+ and Mg2+) in rabbit CSF are unaffected by central IL-i injection (unpublished observations).…”