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

// Jakub Mieczkowski 1, * , Marta Kocyk 1, 2, * , Pawel Nauman 3 , Konrad Gabrusiewicz 1 , Malgorzata Sielska 1 , Piotr Przanowski 1 , Marta Maleszewska 1 , Wenson D. Rajan 1 , Dominika Pszczolkowska 1 , Tomasz Tykocki 3 , Wieslawa Grajkowska 4 , Katarzyna Kotulska 5 , Marcin Roszkowski 6 , Boguslaw Kostkiewicz 7 , Bozena Kaminska 1 1 Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland 2 Postgraduate School of Molecular Medicine, Medical University of Warsaw, Poland 3 Department of Neurosurgery, Institute Psychiatry and Neurology, Warsaw, Poland 4 Departments of Pathology, The Children's Memorial Health Institute, Warsaw, Poland 5 Neurology, The Children's Memorial Health Institute, Warsaw, Poland 6 Neurosurgery, The Children's Memorial Health Institute, Warsaw, Poland 7 Central 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.