{"doi":"10.1371/journal.ppat.1011771","title":"KSHV vIL-6 enhances inflammatory responses by epigenetic reprogramming","abstract":"Kaposi sarcoma-associated herpesvirus (KSHV) inflammatory cytokine syndrome (KICS) is a newly described chronic inflammatory disease condition caused by KSHV infection and is characterized by high KSHV viral load and sustained elevations of serum KSHV-encoded IL-6 (vIL-6) and human IL-6 (hIL-6). KICS has significant immortality and greater risks of other complications, including malignancies. Although prolonged inflammatory vIL-6 exposure by persistent KSHV infection is expected to have key roles in subsequent disease development, the biological effects of prolonged vIL-6 exposure remain elusive. Using thiol(SH)-linked alkylation for the metabolic (SLAM) sequencing and Cleavage Under Target & Release Using Nuclease analysis (CUT&RUN), we studied the effect of prolonged vIL-6 exposure in chromatin landscape and resulting cytokine production. The studies showed that prolonged vIL-6 exposure increased Bromodomain containing 4 (BRD4) and histone H3 lysine 27 acetylation co-occupancies on chromatin, and the recruitment sites were frequently co-localized with poised RNA polymerase II with associated enzymes. Increased BRD4 recruitment on promoters was associated with increased and prolonged NF-κB p65 binding after the lipopolysaccharide stimulation. The p65 binding resulted in quicker and sustained transcription bursts from the promoters; this mechanism increased total amounts of hIL-6 and IL-10 in tissue culture. Pretreatment with the BRD4 inhibitors, OTX015 and MZ1, eliminated the enhanced inflammatory cytokine production. These findings suggest that persistent vIL-6 exposure may establish a chromatin landscape favorable for the reactivation of inflammatory responses in monocytes. This epigenetic memory may explain the greater risk of chronic inflammatory disease development in KSHV-infected individuals.","journal":"PLoS Pathogens","year":2023,"id":359894,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9569,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":444449,"name":"Kang-Hsin Wang","orcid":null,"position":1,"is_corresponding":false},{"id":509670,"name":"Ashish Kumar","orcid":"0000-0002-9476-7784","position":2,"is_corresponding":false},{"id":510788,"name":"Chie Izumiya","orcid":null,"position":3,"is_corresponding":false},{"id":1110869,"name":"Hiroki Miura","orcid":"0000-0002-2847-3374","position":4,"is_corresponding":false},{"id":1111355,"name":"Somayeh Komaki","orcid":null,"position":5,"is_corresponding":false},{"id":62279,"name":"Ryan R. Davis","orcid":"0000-0001-7439-6683","position":6,"is_corresponding":false},{"id":640727,"name":"Clifford G. Tepper","orcid":"0000-0001-7105-1102","position":7,"is_corresponding":false},{"id":1110870,"name":"Harutaka Katano","orcid":"0000-0002-5332-4434","position":8,"is_corresponding":false},{"id":281714,"name":"Michiko Shimoda","orcid":"0000-0002-6627-4624","position":9,"is_corresponding":false},{"id":475386,"name":"Yoshihiro Izumiya","orcid":"0000-0002-9184-2603","position":10,"is_corresponding":false},{"id":864623,"name":"Tomoki Inagaki","orcid":"0009-0007-2332-9895","position":0,"is_corresponding":true}],"reference_count":85,"raw_metadata":null,"created_at":"2026-07-19T01:13:57.361401Z","pmid":"37934757","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":[]}