IL-33 induces ADAMTS5 expression and cell migration in glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM), characterized by a high rate of proliferation and migration capacity, is an incurable brain tumor in adults. , a member of the IL-1 cytokine superfamily and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), a family of zinc dependent metalloproteinases are known to have an essential roles in GBM migration and invasion. Previous studies have separately revealed elevated expressions of IL-33 and ADAMTS5 in GBM; however, the interaction between IL-33 and ADAMTS5 in GBM pathogenesis has remained unclear. Here, using publically available GlioVis and GEPIA programs, we showed that mRNA expression of IL-33 and ADAMTS5 is signi cantly high in GBM cells, and a positive correlation between IL-33 and ADAMTS5 was also determined in these cells. In parallel with the mRNA data of IL-33 and ADAMTS5, by Western blot analysis, protein levels were found to be elevated in GBM tissues and increased gradually with the disease progression. Primary GBM cells and low-grade glioma cells were then treated with IL-33 to examine its stimulating effect on ADAMTS5 expression. Exposure to IL-33 raised ADAMTS5 protein levels in a dose-dependent manner. Finally, the wound healing method was performed to con rm the impact of IL-33 on migration in primary GBM cells. IL-33 promoted migration of primary GBM cells three-times higher than untreated GBM cells. Thus, the current study suggests for the rst time that IL-33 might have a role in play a part in GBM progression through induction of ADAMTS5 expression and promotion of migration in GBM cells.

Modulation of Neuroinflammation: Advances in Roles and Mechanisms of the IL-33/ST2 Axis Involved in Ischemic Stroke

“…Moreover, numerous studies have identified that IL-33 has a dual function as a coordinator of the glioblastoma microenvironment, which ultimately contributes to tumorigenesis [37][38][39][40]. Its nuclear and secreted functions may promote chemokine recruitment and activate innate immune cells, establishing a pro-tumorigenic environment in glioblastoma [38].…”

Epigenetic Underpinnings of Inflammation: A Key to Unlock the Tumor Microenvironment in Glioblastoma

“…Meanwhile, IL-1b also activates the p38 mitogen-activated protein kinase (MAPK)activated protein kinase 2 (MK2)-human antigen R (HuR), tolllike receptor 4 (TLR-4), and other inflammation-associated signaling pathways that significantly increase the levels of IL-6 and IL-8 in GBM tumor cells, eventually developing an inflammatory TME in favor of GBM invasion and growth (61)(62)(63). Additionally, IL-33 induced by GBM tumor cells is another important inflammatory mediator that accelerates GBM proliferation, migration, and invasion (47,64,65). Interestingly, IL-33 could transform non-stem cells to GBM stem cells (66), activate disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and EGFR by promoting the accumulation of tenascin-C (TNC), which in turn exacerbates GBM tumor cell proliferation (47,64,65,67).…”

“…Additionally, IL-33 induced by GBM tumor cells is another important inflammatory mediator that accelerates GBM proliferation, migration, and invasion (47,64,65). Interestingly, IL-33 could transform non-stem cells to GBM stem cells (66), activate disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and EGFR by promoting the accumulation of tenascin-C (TNC), which in turn exacerbates GBM tumor cell proliferation (47,64,65,67). Both subfamilies of IL-1 accelerate GBM relapse, however, blocking IL-1b and IL-33 can reduce tumor progression-associated compensation mechanisms including the Warburg effect (47,68).…”