Oncotarget

Research Papers:

Down-regulation of IKKβ expression in glioma-infiltrating microglia/macrophages is associated with defective inflammatory/immune gene responses in glioblastoma

Jakub Mieczkowski _, Marta Kocyk, Pawel Nauman, Konrad Gabrusiewicz, Małgorzata Sielska, Piotr Przanowski, Marta Maleszewska, Wenson D. Rajan, Dominika Pszczolkowska, Tomasz Tykocki, Wieslawa Grajkowska, Katarzyna Kotulska, Marcin Roszkowski, Boguslaw Kostkiewicz and Bozena Kaminska

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Oncotarget. 2015; 6:33077-33090. https://doi.org/10.18632/oncotarget.5310

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Abstract

Jakub Mieczkowski1,*, Marta Kocyk1,2,*, Pawel Nauman3, Konrad Gabrusiewicz1, Małgorzata Sielska1, Piotr Przanowski1, Marta Maleszewska1, Wenson D. Rajan1, Dominika Pszczolkowska1, Tomasz Tykocki3, Wieslawa Grajkowska4, Katarzyna Kotulska5, Marcin Roszkowski6, Boguslaw Kostkiewicz7, Bozena Kaminska1

1Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland

2Postgraduate School of Molecular Medicine, Medical University of Warsaw, Poland

3Department of Neurosurgery, Institute Psychiatry and Neurology, Warsaw, Poland

4Departments of Pathology, The Children's Memorial Health Institute, Warsaw, Poland

5Neurology, The Children's Memorial Health Institute, Warsaw, Poland

6Neurosurgery, The Children's Memorial Health Institute, Warsaw, Poland

7Central Clinical Hospital Ministry of Interior, Warsaw, Poland

*These authors have contributed equally to this work

Correspondence to:

Bozena Kaminska, e-mail: bozenakk@nencki.gov.pl

Keywords: immunosuppression, glioma-associated microglia/macrophages, global gene expression profiling, glioblastoma, IKKβ/NFkB signaling

Received: April 03, 2015     Accepted: September 17, 2015     Published: September 29, 2015

ABSTRACT

Glioblastoma (GBM) is an aggressive malignancy associated with profound host immunosuppression. Microglia and macrophages infiltrating GBM acquire the pro-tumorigenic, M2 phenotype and support tumor invasion, proliferation, survival, angiogenesis and block immune responses both locally and systematically. Mechanisms responsible for immunological deficits in GBM patients are poorly understood. We analyzed immune/inflammatory gene expression in five datasets of low and high grade gliomas, and performed Gene Ontology and signaling pathway analyses to identify defective transcriptional responses. The expression of many immune/inflammatory response and TLR signaling pathway genes was reduced in high grade gliomas compared to low grade gliomas. In particular, we found the reduced expression of the IKBKB, a gene coding for IKKβ, which phosphorylates IκB proteins and represents a convergence point for most signal transduction pathways leading to NFκB activation. The reduced IKBKB expression and IKKβ levels in GBM tissues were demonstrated by qPCR, Western blotting and immunohistochemistry. The IKKβ expression was down-regulated in microglia/macrophages infiltrating glioblastoma. NFκB activation, prominent in microglia/macrophages infiltrating low grade gliomas, was reduced in microglia/macrophages in glioblastoma tissues. Down-regulation of IKBKB expression and NFκB signaling in microglia/macrophages infiltrating glioblastoma correlates with defective expression of immune/inflammatory genes and M2 polarization that may result in the global impairment of anti-tumor immune responses in glioblastoma.


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