A Study of Nuclear Transcription Factor-Kappa B in Childhood Autism

BACKGROUND: Several children with autism show regression in language and social development while maintaining normal motor milestones. A clear period of normal development followed by regression and subsequent improvement with treatment, suggests a multifactorial etiology. The role of inflammation in autism is now a major area of study. Viral and bacterial infections, hypoxia, or medication could affect both foetus and infant. These stressors could upregulate transcription factors like nuclear factor kappa B (NF-κB), a master switch for many genes including some implicated in autism like tumor necrosis factor (TNF). On this hypothesis, it was proposed to determine NF-κB in children with autism. METHODS: Peripheral blood samples of 67 children with autism and 29 control children were evaluated for NF-κB using electrophoretic mobility shift assay (EMSA). A phosphor imaging technique was used to quantify values. The fold increase over the control sample was calculated and statistical analysis was carried out using SPSS 15. RESULTS: We have noted significant increase in NF-κB DNA binding activity in peripheral blood samples of children with autism. When the fold increase of NF-κB in cases (n = 67) was compared with that of controls (n = 29), there was a significant difference (3.14 vs. 1.40, respectively; p<0.02). CONCLUSION: This finding has immense value in understanding many of the known biochemical changes reported in autism. As NF-κB is a response to stressors of several kinds and a master switch for many genes, autism may then arise at least in part from an NF-κB pathway gone awry

The high Nrf2 expression in human acute myeloid leukemia is driven by NF-κB and underlies its chemo-resistance

NF-E2-related factor 2 (Nrf2) transcription factor regulates a range of cytoprotective transcriptional responses, preventing further cellular injury by removing biochemical damage and renewing tissue. Here we show that acute myeloid leukemia (AML) cells possess greater constitutive nuclear levels of Nrf2 than normal control CD34(+) cells because of an imbalance between mRNA expression levels of Nrf2 and its inhibitor Keap1 but not through their somatic mutation. Elevated Nrf2 was reduced by NF-κB inhibitors. Using promoter assays, ChIP and siRNA knockdown, we demonstrated NF-κB subunits p50 and p65 induce transcription of Nrf2 in AML cells at a specific promoter κB-site and that long-term lentiviral miRNA-knockdown of Nrf2 significantly reduced clonogenicity of AML patient cells and improved their chemotherapeutic responsiveness. Normal physiologic Nrf2 protects cells from damage, but here we have exposed aberrant continuous nuclear activation of Nrf2 in AML that allows cell survival, even against cytotoxic chemotherapeutics. We show for the first time that Nrf2, an important regulator of several biologic processes involved in the progression of cancer, has abnormal NF-κB-driven constitutive expression in AML. Such a mechanism allows for a greater cytoprotective response in human AML cells and encourages their evasion of chemotherapy-induced cytotoxicity, which is necessary for improved clinical outcomes