Abstract
Background: The recombinant IL-1 receptor antagonist anakinra—currently approved for the treatment of autoinflammatory diseases—blocks IL-1β-mediated inflammatory signaling. As inflammation is a major driver of cancer, we hypothesized that anakinra might be able to mitigate glioblastoma (GBM) aggressiveness. Methods: Primary GBM or T98G cells were incubated alone or with peripheral blood mononuclear cells (PBMCs) and were subsequently treated with IL-1β and/or anakinra. T cells were obtained by magnetic bead isolation. Protein and mRNA expression were quantified by SDS-PAGE, qRT-PCR, and ELISA, respectively. Cell proliferation and apoptosis were analyzed via flow cytometry. Chemotaxis was studied via time-lapse microscopy. Results: Upon IL-1β stimulation, anakinra attenuated proinflammatory gene expression in both GBM cells and PBMCs, and mitigated tumor migration and proliferation. In a more lifelike model replacing IL-1β stimulation by GBM–PBMC co-culture, sole presence of PBMCs proved sufficient to induce a proinflammatory phenotype in GBM cells with enhanced proliferation and migration rates and attenuated apoptosis. Anakinra antagonized these pro-tumorigenic effects and, moreover, reduced inflammatory signaling in T cells without compromising anti-tumor effector molecules. Conclusion: By dampening the inflammatory crosstalk between GBM and immune cells, anakinra mitigated GBM aggressiveness. Hence, counteracting IL-1β-mediated inflammation might be a promising strategy to pursue.
Highlights
Inflammation has emerged as a major promoter of all stages of tumorigenesis [1,2,3]
IL-1β stimulation resulted in a marked increase of the proinflammatory genes IL-1β, COX-2, CCL2, in primary GBM cells and peripheral blood mononuclear cells (PBMC) [17]
We that the IL-1 antagonist anakinra puts the brake on inflammatory gene expression in both GBM and showed that the IL-1 antagonist anakinra puts the brake on inflammatory gene expression in both immune cells, and thereby attenuates GBM cell aggressiveness
Summary
Inflammation has emerged as a major promoter of all stages of tumorigenesis [1,2,3]. Intricate networks of tumor-associated inflammation are driven by a perpetual crosstalk between cancer and tumor-infiltrating immune cells, which has mutually reinforcing effects and boosts the production of cytokine mediators by both immune and tumor cells [4,5,6]. The resulting inflammatory milieu promotes tumor progression, and blocks anti-tumor immunity by impairing functions of the adaptive immune system [7,8]. Interleukin (IL)-1β has emerged as the master cytokine activating inflammatory signaling pathways in both cancer and immune cells [9,10,11]. As inflammation is a major driver of cancer, we hypothesized that anakinra might be able to mitigate glioblastoma (GBM) aggressiveness. Results: Upon IL-1β stimulation, anakinra attenuated proinflammatory gene expression in both GBM cells and PBMCs, and mitigated tumor migration and proliferation. In a more lifelike model replacing IL-1β stimulation by GBM–PBMC co-culture, sole presence of PBMCs proved sufficient to induce a proinflammatory phenotype in GBM cells with enhanced proliferation and migration rates and attenuated apoptosis
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