A novel approach to analyze gene expression data demonstrates that the ΔF508 mutation in CFTR downregulates the antigen presentation pathway

Gene array studies comparing cystic fibrosis (CF) and non-CF genotypes should reveal factors that explain variability in CF lung disease progression, yielding insights that lead to improved CF care. To date, studies have reached conflicting conclusions, perhaps due to experimental differences and divergent statistical approaches. This review aims: 1) to summarize the findings of four recent gene studies comparing CF and non-CF genotypes, and 2) to reanalyze original data using a recently developed statistical approach, with the aim of identifying genes and paths consistently regulated by the CF genotype. We identified four studies evaluating the effect of the ΔF508-CFTR mutation on human airway epithelial cell gene expression, restricting our investigation to human airway epithelial cell studies whose data were accessible in NCBI's Gene Expression Omnibus or the European Bioinformatic Institute's ArrayExpress. Gene expression patterns showed consistent repression of MHC class I antigen presentation genes in CF human airway epithelia, suggesting a novel mechanistic explanation for poor clearance of viral and bacterial infections by CF patients. We also examined proinflammatory and NF-κB genes, whose induction is widely accepted as a hallmark of the CF genotype, but found little evidence of induction, consistent with a recent review (Machen TE, Am J Physiol Cell Physiol 291: C218–C230, 2006.). In conclusion, our analysis suggests that the CF genotype may impair immune function in airway epithelial cells but may not increase inflammation. Additional studies are required to determine whether MHC class I gene repression in CF reduces antigen presentation at the protein level and whether repression impairs immune function

Emerging Evidence for the Importance of Phosphorylation in the Regulation of NADPH Oxidases

The NADPH oxidase (Nox) enzyme family generates reactive oxygen species (ROS) that contribute to cell signaling, innate immune responses, proliferation, and transcription. The signaling mechanisms that regulate this important enzyme family are only beginning to be understood. Evidence is emerging which suggests that phosphorylation of Nox and/or their regulatory components may be important means of modulating their activity. We describe here the evidence for Nox regulation through the action of kinases, and speculate on how such regulatory mechanisms might contribute to the development of pathological disease states. Antioxid. Redox Signal. 11, 2429–2441

Toxicologie predictive: les voies du futur

National audienc

Toxicologie predictive: les voies du futur

National audienc

Toxicologie predictive: les voies du futur

National audienc