RT Journal Article
SR Electronic
T1 CUX1 and IκBζ mediate the synergistic inflammatory response to TNF and IL-17A in stromal fibroblasts
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 571315
DO 10.1101/571315
A1 Kamil Slowikowski
A1 Hung N. Nguyen
A1 Erika H. Noss
A1 Daimon P. Simmons
A1 Fumitaka Mizoguchi
A1 Gerald F.M. Watts
A1 Michael F. Gurish
A1 Michael B. Brenner
A1 Soumya Raychaudhuri
YR 2019
UL http://biorxiv.org/content/early/2019/03/11/571315.abstract
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.