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

SUBMITTER: Mieczkowski J 

PROVIDER: S-EPMC4741750 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature