Activation of glucocorticoid receptor signaling inhibits KSHV-induced inflammation and tumorigenesis

mBio. 2024 Jan 16;15(1):e0301123. doi: 10.1128/mbio.03011-23. Epub 2023 Dec 20.

Abstract

Kaposi's sarcoma (KS) is the most common cancer in HIV-infected patients caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Hyperinflammation is the hallmark of KS. In this study, we have shown that KSHV mediates hyperinflammation by inducing IL-1α and suppressing IL-1Ra. Mechanistically, KSHV miRNAs and vFLIP induce hyperinflammation by activating the NF-κB pathway. A common anti-inflammatory agent dexamethasone blocks KSHV-induced hyperinflammation and tumorigenesis by activating glucocorticoid receptor signaling to suppress IL-1α and induce IL-1Ra. This work has identified IL-1-mediated inflammation as a potential therapeutic target and dexamethasone as a potential therapeutic agent for KSHV-induced malignancies.

Keywords: IL-1 receptor antagonist (IL-1Ra); Kaposi’s sarcoma (KS); Kaposi’s sarcoma-associated herpesvirus (KSHV); NF-κB; dexamethasone; glucocorticoid receptor (GR) signaling; inflammation; interleukin-1 alpha (IL-1α).

MeSH terms

  • Cell Transformation, Neoplastic* / drug effects
  • Cell Transformation, Neoplastic* / metabolism
  • Dexamethasone* / pharmacology
  • Dexamethasone* / therapeutic use
  • Glucocorticoids / pharmacology
  • Glucocorticoids / therapeutic use
  • Herpesvirus 8, Human* / physiology
  • Humans
  • Inflammation / virology
  • Interleukin 1 Receptor Antagonist Protein / metabolism
  • Receptors, Glucocorticoid* / metabolism
  • Sarcoma, Kaposi* / drug therapy

Substances

  • Dexamethasone
  • Glucocorticoids
  • Interleukin 1 Receptor Antagonist Protein
  • Receptors, Glucocorticoid