CUX1 and IκBζ (NFKBIZ) mediate the synergistic inflammatory response to TNF and IL-17A in stromal fibroblasts
Kamil Slowikowski*, Hung N. Nguyen*, Erika H. Noss, Daimon P. Simmons, Fumitaka Mizoguchi, Gerald F.M. Watts, Michael F. Gurish, Michael B. Brenner, Soumya Raychaudhuri
PNAS 2020. doi: 10.1073/pnas.1912702117
Significance
Rheumatoid arthritis is characterized by elevated levels of inflammatory cytokines including TNF and IL-17A. Synovial fibroblasts produce inflammatory factors such as IL-6 in response to TNF, and the addition of IL-17A synergistically amplifies this response. We profiled the transcriptomic response of synovial fibroblasts to TNF and different IL-17A dosages over time, and defined a set of genes induced by the addition of IL-17A. We found that CUX1 and IκBζ (NFKBIZ) mediate leukocyte recruitment by regulating production of multiple cytokines and chemokines. We show that gene targets of CUX1 are elevated in synovial tissue from individuals with rheumatoid arthritis relative to controls. While many studies have focused on leukocytes, our results highlight CUX1 and IκBζ as key regulators of inflammation in synovial fibroblasts.
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