title: p38 MAPK inhibitors attenuate pro-inflammatory cytokine production and the invasiveness of human U251 glioblastoma cells.
abstract: 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.
authors.affiliation: Pharmacy, University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: Yiu To
authors.initials: YT
authors.lastname: Yeung
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Bryce
authors.forename: Seray
authors.initials: S
authors.lastname: Adams
authors.forename: Nady
authors.initials: N
authors.lastname: Braidy
authors.forename: Mari
authors.initials: M
authors.lastname: Konayagi
authors.forename: Kerrie L
authors.initials: KL
authors.lastname: McDonald
authors.forename: Charles
authors.initials: C
authors.lastname: Teo
authors.forename: Gilles J
authors.initials: GJ
authors.lastname: Guillemin
authors.forename: Thomas
authors.initials: T
authors.lastname: Grewal
authors.forename: Lenka
authors.initials: L
authors.lastname: Munoz
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002465:Cell Movement / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D047468:Immunoprecipitation; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D048308:Mitogen-Activated Protein Kinase 14