8 research outputs found
A Systems Biology Approach Utilizing a Mouse Diversity Panel Identifies Genetic Differences Influencing Isoniazid-Induced Microvesicular Steatosis
Isoniazid (INH), the mainstay therapeutic for tuberculosis infection, has been associated with rare but serious hepatotoxicity in the clinic. However, the mechanisms underlying inter-individual variability in the response to this drug have remained elusive. A genetically diverse mouse population model in combination with a systems biology approach was utilized to identify transcriptional changes, INH-responsive metabolites, and gene variants that contribute to the liver response in genetically sensitive individuals. Sensitive mouse strains developed severe microvesicular steatosis compared with corresponding vehicle control mice following 3 days of oral treatment with INH. Genes involved in mitochondrial dysfunction were enriched among liver transcripts altered with INH treatment. Those associated with INH treatment and susceptibility to INH-induced steatosis in the liver included apolipoprotein A-IV, lysosomal-associated membrane protein 1, and choline phosphotransferase 1. These alterations were accompanied by metabolomic changes including reduced levels of glutathione and the choline metabolites betaine and phosphocholine, suggesting that oxidative stress and reduced lipid export may additionally contribute to INH-induced steatosis. Finally, genome-wide association mapping revealed that polymorphisms in perilipin 2 were linked to increased triglyceride levels following INH treatment, implicating a role for inter-individual differences in lipid packaging in the susceptibility to INH-induced steatosis. Taken together, our data suggest that INH-induced steatosis is caused by not one, but multiple events involving lipid retention in the livers of genetically sensitive individuals. This work also highlights the value of using a mouse diversity panel to investigate drug-induced responses across a diverse population
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Glucocorticoid regulation of GM-CSF in bronchial epithelial cells
Inflammation plays a central role in the pathogenesis of asthma. Glucocorticoids are first line antiinflammatory therapy in the treatment of asthma and are effective inhibitors of inflammatory cytokines. Clinical data demonstrate that granulocyte-macrophage colony-stimulating factor (GM-CSF) production by airway epithelial cells may be an important target of inhaled glucocorticoid therapy. In this study, the regulatory mechanisms of GM-CSF expression by interleukin-1β (IL-1β) and the synthetic glucocorticoid dexamethasone (DEX) were examined in the BEAS-2B human bronchial epithelial cell line. It is hypothesized that glucocorticoids inhibit GM-CSF production in these cells through transcriptional mechanisms involving induction of the NF-κB inhibitory protein, IκB-α. Treatment of the BEAS-2B cells with IL-1β induced GM-CSF protein and mRNA levels, and further investigation showed this induction was mediated through transcriptional mechanisms. DEX treatment of BEAS-2B cells inhibited IL-1β-induced GM-CSF protein and mRNA production. GM-CSF mRNA was rapidly degraded in these cells, and DEX treatment did not significantly affect this decay rate. These data suggest that dexamethasone repression of GM-CSF expression is mediated predominantly through transcriptional mechanisms. This study then examined expression of IκB-α in the BEAS-2B cells as a possible mechanism of glucocorticoid repression of GM-CSF. IκB-α RNA levels were minimally induced by DEX in these cells, but this did not result in concurrent induction of IκB-α protein. Additional analysis showed that DEX treatment of BEAS-2B cells did not prevent nuclear translocation of the NF-κB subunit p65, or IL-1β-induced degradation of IκB-α protein. From these data, this study concludes that induction of IκB-α is not a significant mechanism of glucocorticoid-mediated repression of GM-CSF in the BEAS-2B cells