title: Down-regulation of IKKβ expression in glioma-infiltrating microglia/macrophages is associated with defective inflammatory/immune gene responses in glioblastoma.
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.
authors.affiliation: Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Mieczkowski
authors.affiliation: Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.|Postgraduate School of Molecular Medicine, Medical University of Warsaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Kocyk
authors.affiliation: Department of Neurosurgery, Institute Psychiatry and Neurology, Warsaw, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Nauman
authors.affiliation: Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Konrad
authors.initials: K
authors.lastname: Gabrusiewicz
authors.affiliation: Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Sielska
authors.affiliation: Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Przanowski
authors.affiliation: Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Maleszewska
authors.affiliation: Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Wenson D
authors.initials: WD
authors.lastname: Rajan
authors.affiliation: Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Dominika
authors.initials: D
authors.lastname: Pszczolkowska
authors.affiliation: Department of Neurosurgery, Institute Psychiatry and Neurology, Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Tykocki
authors.affiliation: Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Grajkowska
authors.affiliation: Deparment of Neurology, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kotulska
authors.affiliation: Deparment of Neurosurgery, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Roszkowski
authors.affiliation: Central Clinical Hospital Ministry of Interior, Warsaw, Poland.
authors.forename: Boguslaw
authors.initials: B
authors.lastname: Kostkiewicz
authors.affiliation: Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Bozena
authors.initials: B
authors.lastname: Kaminska
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D017628:Microglia / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D051550:I-kappa B Kinase; C496560:IKBKB protein, human
keywords: IKKβ/NFkB signaling; glioblastoma; glioma-associated microglia/macrophages; global gene expression profiling; immunosuppression