Down-regulation of IKKβ expression in glioma-infiltrating microglia/macrophages is associated with defective inflammatory/immune gene responses in glioblastoma
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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
Bozena Kaminska, e-mail: [email protected]
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
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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