IL-4 exploits TNF signaling to shape its gene expression signature in monocytes and macrophages

Investigation of crosstalk between antagonistic pro- and anti-inflammatory cytokines has focused on mechanisms and functional consequences of cross-inhibition. Here, we investigate cross-regulation between proinflammatory tumor necrosis factor (TNF) and anti-inflammatory interleukin-4 (IL-4) in primary human monocytes and in a skin wound-healing model. Surprisingly, TNF functioned mainly as a costimulator of IL-4-induced gene expression, whereas IL-4 selectively inhibited the TNF-induced IFN response, leaving inflammatory gene expression mostly intact. TNF and IL-4 synergistically induced gene sets that are important in the regulation of inflammation and tissue repair, which were highly induced during the phase of wound healing when these cytokines are co-expressed. Crosstalk between TNF and IL-4 was mediated by epigenetic chromatin-mediated mechanisms associated with cooperation between NF-κB and STAT6 transcription factors, erasure of negative histone mark H3K27me3, and selective inhibition of IRF1. These results identify a mechanism for expansion of the IL-4 response and highlight the complexity of crosstalk between antagonistic cytokines, including cooperation for select gene responses that are important for immune responses and tissue repair. Transcriptional and epigenetic mechanisms regulate responses to cytokines, as well as the crosstalk between pro- and anti-inflammatory cytokines. Here, the authors demonstrate that pro-inflammatory TNF amplifies, rather than blocks, the anti-inflammatory IL-4 response in human monocytes and that NF-κB and STAT6 cooperate on chromatin to activate tissue-repair genes.