Role of Tumor Necrosis Factor-α in the Human Systemic Endotoxin-Induced Transcriptome

TNF alpha has been implicated in the pathogenesis of various inflammatory diseases. Different strategies to inhibit TNF alpha in patients with sepsis and chronic inflammatory conditions have shown contrasting outcomes. Although TNF alpha inhibitors are widely used in clinical practice, the impact of TNF alpha antagonism on white blood cell gene expression profiles during acute inflammation in humans in vivo has not been assessed. We here leveraged the established model of human endotoxemia to examine the effect of the TNF alpha antagonist, etanercept, on the genome-wide transcriptional responses in circulating leukocytes induced by intravenous LPS administration in male subjects. Etanercept pre-treatment resulted in a markedly dampened transcriptional response to LPS. Gene co-expression network analysis revealed this LPS-induced transcriptome can be categorized as TNF alpha responsive and non-responsive modules. Highly significant TNF alpha responsive modules include NF-kB signaling, antiviral responses and T-cell mediated responses. Within these TNF alpha responsive modules we delineate fundamental genes involved in epigenetic modifications, transcriptional initiation and elongation. Thus, we provide comprehensive information about molecular pathways that might be targeted by therapeutic interventions that seek to inhibit TNF alpha activity during human inflammatory diseases.