CUX1 and IκBζ mediate the synergistic inflammatory response to TNF and IL-17A in stromal fibroblasts

Abstract

The role of stromal fibroblasts in chronic inflammation is unfolding. In rheumatoid arthritis (RA), leukocyte-derived cytokines tumor necrosis factor (TNF) and IL-17A work together, activating fibroblasts to become a dominant source of the hallmark cytokine IL-6. However, IL-17A alone has minimal effect on fibroblasts. To identify key mediators of the synergistic response to TNF and IL-17A in human synovial fibroblasts, we performed time series, dose response, and gene silencing transcriptomics experiments. Here we show that in combination with TNF, IL-17A selectively induces a specific set of genes mediated by factors including CUX1 and I{kappa}B{zeta}. In the promoters of CXCL1, CXCL2, and CXCL3, we found a putative CUX1-NF-{kappa}B binding motif not found elsewhere in the genome. CUX1 and NF-{kappa}B p65 mediate transcription of these genes independent of LIFR, STAT3, STAT4, and ELF3. Transcription of NFKBIZ, encoding the atypical I{kappa}B factor I{kappa}B{zeta}, is IL-17A dose-dependent, and I{kappa}B{zeta} only mediates the transcriptional response to TNF and IL-17A, but not to TNF alone. In fibroblasts, IL-17A response depends on CUX1 and I{kappa}B{zeta} to engage the NF-{kappa}B complex to produce chemoattractants for neutrophil and monocyte recruitment.