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

View ORCID ProfileKamil Slowikowski, Hung N. Nguyen, Erika H. Noss, Daimon P. Simmons, View ORCID ProfileFumitaka Mizoguchi, Gerald F.M. Watts, Michael F. Gurish, Michael B. Brenner, View ORCID ProfileSoumya Raychaudhuri
doi: https://doi.org/10.1101/571315
Kamil Slowikowski
1Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
2Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
3Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
4Department of Biomedical Informatics, Harvard Medical School, Boston 02115, MA, USA
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Hung N. Nguyen
1Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
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Erika H. Noss
1Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
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Daimon P. Simmons
1Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
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Fumitaka Mizoguchi
5Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
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Gerald F.M. Watts
1Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
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Michael F. Gurish
1Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
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Michael B. Brenner
1Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
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Soumya Raychaudhuri
1Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
2Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
3Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
4Department of Biomedical Informatics, Harvard Medical School, Boston 02115, MA, USA
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Summary

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.

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Posted March 11, 2019.
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CUX1 and IκBζ 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
bioRxiv 571315; doi: https://doi.org/10.1101/571315
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CUX1 and IκBζ 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
bioRxiv 571315; doi: https://doi.org/10.1101/571315

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