P38 MAPK/AKT signalling is involved in IL-33-mediated anti-apoptosis in childhood acute lymphoblastic leukaemia blast cells

Abstract

Background Acute lymphoblastic leukaemia (ALL) is often characterized by broad clinical and biological heterogeneity, as well as recurrent genetic aberrations. Despite remarkable improvements in the treatment outcome in paediatric ALL over the past several decades, it remains a leading cause of morbidity and mortality among children. Cytokines have been extensively studied in haematologic diseases; however, the mechanisms by which cytokines contribute to ALL pathogenesis remain poorly understood. Methods IL-33 levels were measured by enzyme-linked immunosorbent assay (ELISA). IL1RL1 expression on ALL cell surface was accessed by flow cytometry. Expression of phosphorylated p38 MAPK, p38, pAKT, AKT and GAPDH were quantified by western blot. Cell survival signals were evaluated by apoptosis using flow cytometry. Results BM samples from ALL patients at diagnosis upregulated their cell surface expression of IL1RL1, and a higher interleukin (IL)-33 level in the serum was observed as compared to the healthy individuals. Moreover, exogenous IL-33 treatment significantly inhibited apoptosis by activating p38 mitogen-activated protein kinase (MAPK) and AKT pathway, while the inhibitor for p38 MAPK, SB203580, counteracted IL-33-induced anti-apoptosis via inactivation of p38 MAPK and AKT. Furthermore, IL-33 negatively regulates cyclin B1 protein level while increasing the expression of CDK1, with SB203580 inhibiting the effect. Conclusion Our study reveals an important role for IL-33/IL1RL1 axis in supporting ALL which may represent a novel treatment for paediatric patients. KEY MESSAGES Both IL-33 and IL1RL1 levels are upregulated in primary ALL samples. IL-33 increased both p38 MAPK and AKT activation in ALL. IL-33 promotes survival and cell cycle progression of ALL cells via activating p38 MAPK.

Pharmacological p38 MAPK inhibitor SB203580 enhances AML stem cell line KG1a chemosensitivity to daunorubicin by promoting late apoptosis, cell growth arrest in S-phase, and miR-328-3p upregulation

“…6 A). As a p38 MAPK inhibitor, SB203580 was reported to block Akt phosphorylation ( Wang et al, 2021 ). Herein, an obvious decrease in Akt 1/2/3 (S473) phosphorylation level was detected in KG1a cells upon the combination treatment, compared to DNR alone ( Fig.…”

“…Stojak et al (2014) reported G2/M-phase arrest in human AML cell line ML-1 and human acute lymphoblastic leukemia (ALL) cell line MOLT-4 after treating the cells with 50 and 150 nM DNR for 72 h of incubation. Using two acute lymphoblastic leukemia (ALL) cell lines CCRF-CEM and MOLT-4 derived from T lymphocytes, DNR treatment was also reported to cause cell growth arrest in G2/M-phase, accompanied by increased levels of p53 and its target gene cell cycle inhibitor p21 ( Al-Aamri et al, 2019 , Wang et al, 2021 ). Both p53 and p21 indicate cell growth arrest and DNA damage due to intercalation of the DNR between DNA base pairs, causing DNA double-strand breaks and topoisomerase II inhibition.…”

Exploring the Destructive Synergy Between IL-33 and Suilysin Hemolysis on Blood Brain Barrier Stability

“…The p38 MAPK signaling pathway enables the adroit interpretation and response to external signals, effectuating varied biological outcomes despite its ostensibly linear architecture. IL-33 markedly circumvents apoptosis via p38 MAPK and AKT pathway activation, a process antagonized by the p38 MAPK inhibitor, SB203580 [29] . This research unveils IL-33 promotion of inflammatory cytokines IL-6 and IL-8 release via p38 MAPK pathway activation, a phenomenon suppressed by SB203580, but not ERK inhibitors.…”