PT  - JOURNAL ARTICLE
AU  - Slowikowski, Kamil
AU  - Nguyen, Hung N.
AU  - Noss, Erika H.
AU  - Simmons, Daimon P.
AU  - Mizoguchi, Fumitaka
AU  - Watts, Gerald F.M.
AU  - Gurish, Michael F.
AU  - Brenner, Michael B.
AU  - Raychaudhuri, Soumya
TI  - CUX1 and IκBζ mediate the synergistic inflammatory response to TNF and IL-17A in stromal fibroblasts
AID  - 10.1101/571315
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 571315
4099  - http://biorxiv.org/content/early/2019/03/11/571315.short
4100  - http://biorxiv.org/content/early/2019/03/11/571315.full
AB  - 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 IκBζ. In the promoters of CXCL1, CXCL2, and CXCL3, we found a putative CUX1-NF-κB binding motif not found elsewhere in the genome. CUX1 and NF-κB p65 mediate transcription of these genes independent of LIFR, STAT3, STAT4, and ELF3. Transcription of NFKBIZ, encoding the atypical IκB factor IκBζ, is IL-17A dose-dependent, and IκBζ only mediates the transcriptional response to TNF and IL-17A, but not to TNF alone. In fibroblasts, IL-17A response depends on CUX1 and IκBζ to engage the NF-κB complex to produce chemoattractants for neutrophil and monocyte recruitment.