Differential cytokine profiles upon comparing selective versus classic glucocorticoid receptor modulation in human peripheral blood mononuclear cells and inferior turbinate tissue

PLoS One. 2015 Apr 13;10(4):e0123068. doi: 10.1371/journal.pone.0123068. eCollection 2015.

Abstract

Background: Glucocorticoid Receptor agonists, particularly classic glucocorticoids, are the mainstay among treatment protocols for various chronic inflammatory disorders, including nasal disease. To steer away from steroid-induced side effects, novel GR modulators exhibiting a more favorable therapeutic profile remain actively sought after. Currently, the impact of 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride a plant-derived selective glucocorticoid receptor modulator named compound A, on cytokine production in ex vivo human immune cells and tissue has scarcely been evaluated.

Methods and results: The current study aimed to investigate the effect of a classic glucocorticoid versus compound A on cytokine and inflammatory mediator production after stimulation with Staphylococcus aureus-derived enterotoxin B protein in peripheral blood mononuclear cells (PBMCs) as well as in inferior nasal turbinate tissue. To this end, tissue fragments were stimulated with RPMI (negative control) or Staphylococcus aureus-derived enterotoxin B protein for 24 hours, in presence of solvent, or the glucocorticoid methylprednisolone or compound A at various concentrations. Supernatants were measured via multiplex for pro-inflammatory cytokines (IL-1β, TNFα) and T-cell- and subset-related cytokines (IFN-γ, IL-2, IL-5, IL-6, IL-10, and IL-17). In concordance with the previously described stimulatory role of superantigens in the development of nasal polyposis, a 24h Staphylococcus aureus-derived enterotoxin B protein stimulation induced a significant increase of IL-2, IL-1β, TNF-α, and IL-17 in PBMCs and in inferior turbinates and of IL-5 and IFN-γ in PBMCs.

Conclusion: Notwithstanding some differences in amplitude, the overall cytokine responses to methylprednisolone and compound A were relatively similar, pointing to a conserved and common mechanism in cytokine transrepression and anti-inflammatory actions of these GR modulators. Furthermore, these results provide evidence that selective glucocorticoid receptor modulator-mediated manipulation of the glucocorticoid receptor in human tissues, supports its anti-inflammatory potential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / pharmacology
  • Adolescent
  • Adult
  • Anti-Inflammatory Agents / pharmacology
  • Cell Survival / drug effects
  • Cytokines / metabolism*
  • Female
  • Glucocorticoids / pharmacology
  • Humans
  • Inflammation Mediators / metabolism
  • Leukocytes, Mononuclear / drug effects*
  • Leukocytes, Mononuclear / metabolism*
  • Male
  • Methylprednisolone / pharmacology
  • Middle Aged
  • Mifepristone / pharmacology
  • Receptors, Glucocorticoid / agonists
  • Receptors, Glucocorticoid / antagonists & inhibitors
  • Receptors, Glucocorticoid / metabolism*
  • Th1 Cells / drug effects
  • Th1 Cells / metabolism
  • Th2 Cells / drug effects
  • Th2 Cells / metabolism
  • Tyramine / analogs & derivatives
  • Tyramine / pharmacology
  • Young Adult

Substances

  • 2-(4-acetoxyphenyl)-2-chloro-N-methylethylamine
  • Acetates
  • Anti-Inflammatory Agents
  • Cytokines
  • Glucocorticoids
  • Inflammation Mediators
  • Receptors, Glucocorticoid
  • Mifepristone
  • Methylprednisolone
  • Tyramine

Grants and funding

IMB is a postdoctoral fellow of the Research Foundation-Flanders (FWO), grant number 1.2.405.10.N.00 (www.fwo.be). KDB was also supported as a postdoctoral fellow of the FWO (grant number 1.2.546.07.N.01) during the initial stages of this project. The work was funded by a Research Grant of the FWO to KDB (grant number 1.5.107.09.N.00). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.