p38 MAPK inhibitors attenuate pro-inflammatory cytokine production and the invasiveness of human U251 glioblastoma cells

Yiu To Yeung; Nicole S Bryce; Seray Adams; Nady Braidy; Mari Konayagi; Kerrie L McDonald; Charles Teo; Gilles J Guillemin; Thomas Grewal; Lenka Munoz

doi:10.1007/s11060-012-0875-7

p38 MAPK inhibitors attenuate pro-inflammatory cytokine production and the invasiveness of human U251 glioblastoma cells

J Neurooncol. 2012 Aug;109(1):35-44. doi: 10.1007/s11060-012-0875-7. Epub 2012 Apr 19.

Authors

Yiu To Yeung¹, Nicole S Bryce, Seray Adams, Nady Braidy, Mari Konayagi, Kerrie L McDonald, Charles Teo, Gilles J Guillemin, Thomas Grewal, Lenka Munoz

Affiliation

¹ Pharmacy, University of Sydney, Sydney, NSW, 2006, Australia.

PMID: 22528800
DOI: 10.1007/s11060-012-0875-7

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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects
Blotting, Western
Brain Neoplasms / drug therapy
Brain Neoplasms / metabolism
Brain Neoplasms / pathology
Case-Control Studies
Cell Movement / drug effects*
Enzyme Inhibitors / pharmacology*
Flow Cytometry
Glioblastoma / drug therapy
Glioblastoma / metabolism
Glioblastoma / pathology*
Humans
Immunoprecipitation
Inflammation Mediators / metabolism
Interleukin-1beta / metabolism*
Interleukin-6 / metabolism
Interleukin-8 / metabolism
Lipopolysaccharides / pharmacology
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 14 / genetics
Mitogen-Activated Protein Kinase 14 / metabolism*
Neoplasm Invasiveness
RNA, Small Interfering / genetics
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha / metabolism
Wound Healing / drug effects*

Substances

Enzyme Inhibitors
Inflammation Mediators
Interleukin-1beta
Interleukin-6
Interleukin-8
Lipopolysaccharides
RNA, Small Interfering
Tumor Necrosis Factor-alpha
Mitogen-Activated Protein Kinase 14