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

作者：Mieczkowski Jakub; Kocyk Marta; Nauman Pawel; Gabrusiewicz Konrad; Sielska Malgorzata; Przanowski Piotr; Maleszewska Marta; Rajan Wenson D; Pszczolkowska Dominika; Tykocki Tomasz; Grajkowska Wieslawa; Kotulska Katarzyna; Roszkowski Marcin; Kostkiewicz Boguslaw; Kaminska Bozena^*

来源：Oncotarget, 2015, 6(32): 33077-33090.

DOI：10.18632/oncotarget.5310

• immunosuppression
• glioma-associated microglia/macrophages
• global gene expression profiling
• glioblastoma
• IKK beta/NFkB signaling

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 IKK beta, which phosphorylates I kappa B proteins and represents a convergence point for most signal transduction pathways leading to NF kappa B activation. The reduced IKBKB expression and IKK beta levels in GBM tissues were demonstrated by qPCR, Western blotting and immunohistochemistry. The IKK beta expression was down-regulated in microglia/macrophages infiltrating glioblastoma. NF kappa B activation, prominent in microglia/macrophages infiltrating low grade gliomas, was reduced in microglia/macrophages in glioblastoma tissues. Down-regulation of IKBKB expression and NF kappa B 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.

• 出版日期2015-10-20