KSHV vIL-6 enhances inflammatory responses by epigenetic reprogramming

PLoS Pathog. 2023 Nov 7;19(11):e1011771. doi: 10.1371/journal.ppat.1011771. eCollection 2023 Nov.

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.

MeSH terms

  • Cell Cycle Proteins / metabolism
  • Chromatin / metabolism
  • Cytokines / metabolism
  • Epigenesis, Genetic
  • Herpesviridae Infections* / metabolism
  • Herpesvirus 8, Human* / physiology
  • Humans
  • Interleukin-6 / metabolism
  • Nuclear Proteins / metabolism
  • Sarcoma, Kaposi*
  • Transcription Factors / metabolism

Substances

  • Interleukin-6
  • Nuclear Proteins
  • Transcription Factors
  • Cytokines
  • Chromatin
  • BRD4 protein, human
  • Cell Cycle Proteins