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.

IL‐1 family in breast cancer: Potential interplay with leptin and other adipocytokines

“…RecIL-1ra drug development has been also reported at a preclinical stage in murine models of melanoma [31] and fibrosarcoma [32] where sustained IL-1ra was delivered in vivo from biodegradable microspheres. Additionally, IL-1ra blocked IL-1 induced production of colony-stimulating growth factors (CSF) by fibroblasts, lymphocytes and monocytes in acute and chronic myelogenous leukemias [33,34]. All these data confirm that recombinant IL-1 receptor antagonist is a potential drug in cancer treatment [14].…”

Role of Interleukin‐l in Infectious Diseases

“…Prevention of cell-cell contact prevents IL-IRa synthesis but augments IL-1^ production (Poutsiaka et al 1991), IL-4 suppresses LPS-induced IL-1^ gene expression and synthesis but upregulates IL-IRa production (Vannier et al 1992). The dysregulation in production of the agonist and antagonist in human disease has recently been studied by Rambaldi and Cozzolino who examined spontaneous gene expression for IL-1^ and IL-IRa in fresh cells from patients with acute myelogenous leukemia (Rambaldi et al 1991). Cells from each of 11 patients studied spontaneously expressed the gene for IL-\^ whereas the leukemic cells from only 1 of 11 patients expressed IL-IRa following stimulation.…”

Interleukin 1 receptor antagonist (IL1RA) in acute leukaemia: IL1RA is both secreted spontaneously by myelogenous leukaemia blasts and is a part of the acute phase reaction in patients with chemotherapy‐ induced leucopenia

“…Two IL1 receptors have been detected (Type I and Type I1 receptors), and for most cells both ILla and ILlp can bind to both these receptors (1). Several cells, including acute myelogenous leukaemia (AML) blasts, secrete ILla and ILlp together with the ILl receptor antagonist (ILlRA) which blocks IL1 binding to Type 1 and Type 2 IL1 receptors (1,4), and addition of exogenous ILlRA further inhibits autocrine AML blast proliferation and cytokine secretion in vitro ( 4 , 5).…”

“…Severe chemotherapy-induced leucopenia is seen after intensive chemotherapy in acute leukaemia, but despite their severely immunocompromised status these patients show complex alterations in the cytokine network in response to bacterial infections (6)(7)(8)(9)(10). In leukaemia patients in vivo modulation of the cytokine network may become a therapeutic approach for inhibition of potentially harmful proinflammatory effects or for enhancement of antileukaemic effects (1,4,(11)(12)(13)(14), and the cytokines and their antagonists have then been suggested as possible targets for in vivo modulation. First cytokines may be combined with chemotherapy to increase AML blast proliferation and thereby render the blasts more susceptible to cell cyclespecific cytotoxic drugs (15)(16)(17).…”