Cross-regulation of Toll-like receptor responses by cytokines is essential for effective host defense, avoidance of toxicity, and homeostasis, but the underlying mechanisms are not well understood. A comprehensive epigenomic approach in human macrophages showed that the proinflammatory cytokines TNF and type I IFNs induce transcriptional cascades that alter chromatin states to broadly reprogram TLR4-induced responses. TNF tolerized inflammatory genes to prevent toxicity, while preserving antiviral and metabolic gene induction. Type I IFNs potentiated TNF inflammatory function by priming chromatin to prevent silencing of inflammatory NF-κB target genes. Priming of chromatin enabled robust transcriptional responses to weak upstream signals. Similar chromatin regulation occurred in human diseases. Our findings reveal that signaling crosstalk between IFNs and TNF is integrated at the level of chromatin to reprogram inflammatory responses, and identify new functions and mechanisms of action of these cytokines.