Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2020 Mar 10;117(10):5532-5541. doi: 10.1073/pnas.1912702117. Epub 2020 Feb 20.

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

Author information

1
Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
2
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
3
Broad Institute of MIT and Harvard, Cambridge, MA 02142.
4
Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115.
5
Center for Data Sciences, Brigham and Women's Hospital, Boston, MA 02115.
6
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
7
Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-8519 Tokyo, Japan.
8
Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; mbrenner@research.bwh.harvard.edu soumya@broadinstitute.org.
9
Centre for Genetics and Genomics Versus Arthritis, Manchester Academic Health Science Centre, University of Manchester, M13 9PL Manchester, United Kingdom.

Abstract

The role of stromal fibroblasts in chronic inflammation is unfolding. In rheumatoid arthritis, leukocyte-derived cytokines 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 cut-like homeobox 1 (CUX1) and IκBζ (NFKBIZ). 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.

KEYWORDS:

RNA-seq; inflammation; regulation; time series; transcription

PMID:
32079724
PMCID:
PMC7071902
[Available on 2020-08-20]
DOI:
10.1073/pnas.1912702117

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center