p38 MAPK inhibitors attenuate pro-inflammatory cytokine production and the invasiveness of human U251 glioblastoma cells
Increasing evidence suggests that an inflammatory microenvironment promotes invasion by glioblastoma (GBM) cells. Together with p38 mitogen-activated protein kinase (MAPK) activation being regarded as promoting inflammation, we hypothesized that elevated inflammatory cytokine secretion and p38 MAPK activity contribute to expansion of GBMs. Here we report that IL-1β, IL-6, and IL-8 levels and p38 MAPK activity are elevated in human glioblastoma specimens and that p38 MAPK inhibitors attenuate the secretion of pro-inflammatory cytokines by microglia and glioblastoma cells. RNAi knockdown and immunoprecipitation experiments suggest that the p38α MAPK isoform drives inflammation in GBM cells. Importantly, p38 MAPK inhibition strongly reduced invasion of U251 glioblastoma cells in an inflammatory microenvironment, providing evidence for a p38 MAPK-regulated link between inflammation and invasiveness in GBM pathophysiology.
KeywordsGlioblastoma Tumour microenvironment p38 MAPK inhibitors Inflammation Invasion
This study was supported by grants from the Cure for Life Foundation, Alzheimer’s Australia, and The JR and JO Wicking Foundations (managed by ANZ Trustees) to LM; the National Health and Medical Research Council of Australia (510293, 510294) and the University of Sydney (2010-02681) to TG; the Australian Research Council (DP1094232) to NB, and the National Health and Medical Research Council of Australia (1009914) to GG. The authors acknowledge scientific and technical input and support from the Australian Microscopy and Microanalysis Research Facility (AMMRF) at the University of Sydney.
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