PMID- 37934757 OWN - NLM STAT- MEDLINE DCOM- 20231120 LR - 20240210 IS - 1553-7374 (Electronic) IS - 1553-7366 (Print) IS - 1553-7366 (Linking) VI - 19 IP - 11 DP - 2023 Nov TI - KSHV vIL-6 enhances inflammatory responses by epigenetic reprogramming. PG - e1011771 LID - 10.1371/journal.ppat.1011771 [doi] LID - e1011771 AB - 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-kappaB 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. CI - Copyright: (c) 2023 Inagaki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. FAU - Inagaki, Tomoki AU - Inagaki T AUID- ORCID: 0009-0007-2332-9895 AD - Department of Dermatology, School of Medicine, the University of California Davis (UC Davis), Sacramento, California, United States of America. FAU - Wang, Kang-Hsin AU - Wang KH AD - Department of Dermatology, School of Medicine, the University of California Davis (UC Davis), Sacramento, California, United States of America. FAU - Kumar, Ashish AU - Kumar A AD - Department of Dermatology, School of Medicine, the University of California Davis (UC Davis), Sacramento, California, United States of America. FAU - Izumiya, Chie AU - Izumiya C AD - Department of Dermatology, School of Medicine, the University of California Davis (UC Davis), Sacramento, California, United States of America. FAU - Miura, Hiroki AU - Miura H AD - Department of Dermatology, School of Medicine, the University of California Davis (UC Davis), Sacramento, California, United States of America. FAU - Komaki, Somayeh AU - Komaki S AD - Department of Dermatology, School of Medicine, the University of California Davis (UC Davis), Sacramento, California, United States of America. FAU - Davis, Ryan R AU - Davis RR AD - Department of Pathology and Laboratory Medicine, School of Medicine, UC Davis, Sacramento, California, United States of America. FAU - Tepper, Clifford G AU - Tepper CG AD - Department of Biochemistry and Molecular Medicine, School of Medicine, UC Davis, Sacramento, California, United States of America. FAU - Katano, Harutaka AU - Katano H AD - Department of Pathology, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan. FAU - Shimoda, Michiko AU - Shimoda M AD - Department of Dermatology, School of Medicine, the University of California Davis (UC Davis), Sacramento, California, United States of America. FAU - Izumiya, Yoshihiro AU - Izumiya Y AUID- ORCID: 0000-0002-9184-2603 AD - Department of Dermatology, School of Medicine, the University of California Davis (UC Davis), Sacramento, California, United States of America. AD - Department of Biochemistry and Molecular Medicine, School of Medicine, UC Davis, Sacramento, California, United States of America. LA - eng GR - P30 CA093373/CA/NCI NIH HHS/United States GR - R01 CA232845/CA/NCI NIH HHS/United States GR - R01 AI167663/AI/NIAID NIH HHS/United States GR - R01 CA225266/CA/NCI NIH HHS/United States GR - R21 AI155515/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20231107 PL - United States TA - PLoS Pathog JT - PLoS pathogens JID - 101238921 RN - 0 (Interleukin-6) RN - 0 (Nuclear Proteins) RN - 0 (Transcription Factors) RN - 0 (Cytokines) RN - 0 (Chromatin) RN - 0 (BRD4 protein, human) RN - 0 (Cell Cycle Proteins) SB - IM UOF - bioRxiv. 2023 Jul 23;:. PMID: 37503036 MH - Humans MH - *Herpesvirus 8, Human/physiology MH - Interleukin-6/metabolism MH - Nuclear Proteins/metabolism MH - Transcription Factors/metabolism MH - Cytokines/metabolism MH - *Herpesviridae Infections/metabolism MH - Chromatin/metabolism MH - Epigenesis, Genetic MH - *Sarcoma, Kaposi MH - Cell Cycle Proteins/metabolism PMC - PMC10656005 COIS- I have read the journal's policy and the authors of this manuscript have the following competing interests: M.S. and Y.I. are founders of VGN BIO, Inc. and have a pending patent application for the use of vIL-6 for therapeutic purposes. No other authors have financial interests. EDAT- 2023/11/07 18:42 MHDA- 2023/11/20 06:55 PMCR- 2023/11/07 CRDT- 2023/11/07 13:34 PHST- 2023/07/21 00:00 [received] PHST- 2023/10/23 00:00 [accepted] PHST- 2023/11/17 00:00 [revised] PHST- 2023/11/20 06:55 [medline] PHST- 2023/11/07 18:42 [pubmed] PHST- 2023/11/07 13:34 [entrez] PHST- 2023/11/07 00:00 [pmc-release] AID - PPATHOGENS-D-23-01218 [pii] AID - 10.1371/journal.ppat.1011771 [doi] PST - epublish SO - PLoS Pathog. 2023 Nov 7;19(11):e1011771. doi: 10.1371/journal.ppat.1011771. eCollection 2023 Nov.