Interleukin‐1 and interleukin‐2 control granulocyte‐ and granulocyte‐macrophage colony‐stimulating factor gene expression and cell proliferation in cultured acute myeloblastic leukemia

Abstract

In vitro proliferation of leukemic cells purified from 10 cases of acute myeloblastic leukemia (AML) was analyzed in basal conditions or in the presence of exogenous recombinant (r) Interleukin (IL) I. In parallel, blasts from 5 of these patients were studied for granulocyte-macrophage colonystimulating factor (GM-CSF) or granulocyte-CSF (G-CSF) mRNA. 11-1 augmented the spontaneous AML cell proliferation in all cases and induced de novo expression or increased amounts of GM-CSF and/or G-CSF transcripts in 4 of the 5 cases evaluated. IL-I -induced AML cell proliferation was modulated by neutralizing anti-GM-CSF or anti-G-CSF antibodies in those cases in which CSF mRNAs were induced or increased by exogenous cytokine. In the same cases, biosynthetic labelling and immunoprecipitation studies using monospecific anti-GM-CSF antibodies showed that IL-l also increased the levels of GM-CSF protein synthesis. Addition of neutralizing anti-lL-I antibodies to AML cell cultures completely abolished ongoing GM-CSF synthesis, suggesting that endogenous IL-I is needed to maintain autocrine production of CSFs. The effects of rlL-2 were investigated in a larger series of 21 patients. The cytokine reduced spontaneous AML cell proliferation in 8 cases. It caused complete disappearance of GM-CSF mRNA in I case, and marked reduction of G-CSF mRNA in 2 cases. Increased AML cell proliferation was observed in 2 of 21 cases. These findings suggest that expression of CSF genes and cell proliferation in AML are under the control of different cytokines acting in autocrine or paracrine fashion.

Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia

“…Further, our results demonstrated that IL-1-sensitive AML patients clustered with other known myeloid growth-promoting cytokines such as GM-CSF and IL-3. While previous studies describe an effect of IL-1 predominantly on the production of GM-CSF and G-CSF by AML blasts (Bradbury et al, 1990; Cozzolino et al, 1990; Delwel et al, 1989), we show that IL-1 enhances the production of numerous other pro-inflammatory cytokines (e.g. IL-6, IL-8, MCP-1, MIP-1α, MIP-1β) from AML progenitors and blocking IL-1 signaling may mitigate these effects.…”

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

“…Multiple studies have shown that interference with IL-1 signaling by anti-IL-1 antibodies or an IL1R1 antagonist (IL1RA) suppress proliferation of leukemic cells from a majority of AML patients (15)(16)(17)(18)(19)(20)(21)(22)(23). We therefore investigated the ability of the developed antibodies to inhibit IL-1 signaling.…”

Interleukin-1, interleukin-1 receptor, and interleukin-1 receptor antagonist

“…IL-1 has been demonstrated to be spontaneously produced in cultured cells of patients with AML cells. IL-1 also induces the synthesis of colony-stimulating factors (CSF) and sustains leukaemic growth (Cozzolino et al 1990;Rodriguez-Cimadevilla et d. 1990). Recent studies have revealed that the use of IL-lra on proliferate blast cells from the marrow of patients with AML inhibits their spontaneous proliferation in a dosedependent fashion.…”