{"doi":"10.1073/pnas.1912702117","title":"CUX1 and IκBζ (NFKBIZ) mediate the synergistic inflammatory response to TNF and IL-17A in stromal fibroblasts","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.","journal":"Proceedings of the National Academy of Sciences","year":2020,"id":55291,"datarank":2.8385429493212406,"base_score":4.564348191467836,"endowment":4.564348191467836,"self_citation_contribution":0.6846522287201755,"citation_network_contribution":2.153890720601065,"self_endowment_contribution":0.6846522287201755,"citer_contribution":2.153890720601065,"corpus_percentile":null,"corpus_rank":null,"citation_count":95,"citer_count":83,"citers_with_citation_signal":64,"citers_with_endowment":64,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9594,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":285743,"name":"Hung N. Nguyen","orcid":"0000-0003-1084-3725","position":1,"is_corresponding":false},{"id":285744,"name":"Erika H. Noss","orcid":"0000-0001-5712-3579","position":2,"is_corresponding":false},{"id":285745,"name":"Daimon P. Simmons","orcid":"0000-0003-1429-4073","position":3,"is_corresponding":false},{"id":226242,"name":"Fumitaka Mizoguchi","orcid":"0000-0002-3956-7122","position":4,"is_corresponding":false},{"id":226211,"name":"Gerald F. Watts","orcid":"0000-0003-2276-1524","position":5,"is_corresponding":false},{"id":285746,"name":"Michael F. Gurish","orcid":"0000-0002-7893-3156","position":6,"is_corresponding":false},{"id":76152,"name":"Michael B. Brenner","orcid":"0000-0001-6202-8445","position":7,"is_corresponding":false},{"id":35259,"name":"Soumya Raychaudhuri","orcid":"0000-0002-1901-8265","position":8,"is_corresponding":false},{"id":55718,"name":"Kamil Slowikowski","orcid":"0000-0002-2843-6370","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T21:04:59.506324Z","pmid":"32079724","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}