Interleukin-33 Promotes Cell Survival via P38 MAPK-mediated Interleukin-6 Gene Expression and Release in Pediatric AML

Abstract

BackgroundAcute myeloid leukemia (AML) is a fatal disease characterized by an accumulation of immature myeloid blasts in the bone marrow (BM). Cytokine provide signals for leukemia cell to better survive in the BM microenvironment. Previously, we identified interleukin-33 (IL-33) as a stimulator of cell survival in human AML cell line and primary mouse leukemia cells. However, the mechanism on how IL-33 regulates AML activity is not well known.MethodsFlow cytometry, ELISA and cytometric bead array (CBA) were used to investigate the expression of IL1RL1 and serum cytokine levels in AML patient samples and cell culture supernatant. The correlation of serum IL-33 and IL-6 levels was calculated by Pearson R test. Annexin V staining was used to examine the apoptosis of AML cells. RT-PCR was used to measure IL-6 expression in leukemia cells.ResultsThe cell surface expression of IL-33-specific receptor, IL1RL1, is elevated in BM cells from AML patients at diagnosis, and the serum level of IL-33 in AML patients is higher than that of healthy donor controls. Moreover, IL-33 levels are positively associated with IL-6 levels in pediatric patients with AML. In vitro, IL-33 treatment increased IL-6 mRNA expression and protein level in BM and peripheral blood (PB) cells from AML patients. IL-33 inhibited cell apoptosis by activating p38 MAPK pathway using human AML cell line as well as AML patient samples. Finally, IL-33 activated IL-6 expression in a manner that required p38 MAPK pathway using clinical AML samples.ConclusionsTaken together, we demonstrate that p38 MAPK pathway is important for IL-33-mediated anti-apoptotic process as well as cytokine expression and release in pediatric patients with AML.