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

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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.

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Acknowledgments

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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Authors and Affiliations

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

    Yiu To Yeung, Mari Konayagi & Thomas Grewal

  2. School of Chemistry, University of Sydney, Sydney, NSW, 2006, Australia

    Nicole S. Bryce

  3. School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia

    Seray Adams, Nady Braidy, Kerrie L. McDonald & Gilles J. Guillemin

  4. Cure for Life Neuro-Oncology Group, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, 2052, Australia

    Kerrie L. McDonald

  5. Centre for Minimally Invasive Neurosurgery, Prince of Wales Private Hospital, Sydney, NSW, 2052, Australia

    Charles Teo

  6. Department of Neuroimmunology, St. Vincent’s Centre for Applied Medical Research, St. Vincent’s Hospital, Darlinghurst, NSW, 2010, Australia

    Gilles J. Guillemin

  7. School of Medical Sciences (Pharmacology), University of Sydney, Sydney, NSW, 2006, Australia

    Lenka Munoz

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  1. Yiu To Yeung
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  2. Nicole S. Bryce
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  8. Gilles J. Guillemin
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  9. Thomas Grewal
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Correspondence to Thomas Grewal or Lenka Munoz.

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Yeung, Y.T., Bryce, N.S., Adams, S. et al. p38 MAPK inhibitors attenuate pro-inflammatory cytokine production and the invasiveness of human U251 glioblastoma cells. J Neurooncol 109, 35–44 (2012). https://doi.org/10.1007/s11060-012-0875-7

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  • DOI: https://doi.org/10.1007/s11060-012-0875-7

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