Acute serum protein and cytokine response of single dose of prednisone in adult volunteers

• Published in: Steroids 2022-02, Vol.178, p.108953-108953, Article 108953
• Main Authors: Roy, Runia, Soldin, Steven J., Stolze, Brian, Barbieri, Marissa, Tawalbeh, Shefa M., Rouhana, Nicole, Fronczek, Ann E., Nagaraju, Kanneboyina, van den Anker, John, Dang, Utkarsh J., Hoffman, Eric P.
• Format: Article
• Language: English
• Subjects: Blood Proteins; Corticosteroids; Cytokines - genetics; Glucocorticoids - therapeutic use; Humans; IL-10; IL-8; Pharmacodynamic biomarkers; Prednisone; Prednisone - pharmacology; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Tumor Necrosis Factor Ligand Superfamily Member 15; Volunteers; Young Adult
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2021.108953

[Display omitted] •Pharmacodynamic biomarkers after a single 0.2 mg/kg dose in volunteers were studied.•Acute serum time series on both circadian day and drug day were analyzed.•Broad suppression of adrenal steroids by 3 h after dosing was shown.•IL-10 was observed to increase while IL-8 decreased.•Beta-2 microglobulin, TNFSF15, TSH, CST3, NBL1 showed time-related decreases. Pharmacological glucocorticoids are the most prescribed anti-inflammatory medications, and are chemical variants of cortisol, the circadian and stress hormone. Both endogenous and pharmacological glucocorticoids bind the glucocorticoid receptor (NR3C1) with high affinity, and both then bind downstream gene promoter elements (GRE) to drive positive gene transcription of many proteins. Glucocorticoid/GR complexes also bind distinct negative gene promoter elements (nGRE) to inhibit expression of genes involved in NF-κB innate immunity signaling. We sought to define the acute response of a single dose of prednisone (0.2 mg/kg) in young adult volunteers, with blood samples taken at baseline, 2, 3, 4 and 6 h post-oral dose. To control for circadian morning cortisol hitting the same molecular pathways, a day of blood draws was done without oral prednisone (same time of day), one day prior to drug day. Serum samples were processed for steroid hormone profiles (mass spectrometry; 9 steroidal hormones), proteomics (SOMAscan aptamer panels, 1,305 proteins), and inflammatory markers (Meso Scale Discovery; 10 pro-inflammatory cytokines). The pharmacological effect of the prednisone dose was shown by significant declines of adrenal steroids by 3 h after dosing. IL-10 showed drug-related increase to 4 hrs, then decrease to 6 hrs. IL-8 showed drug-related decrease in serum by 4 h, consistent with direct negative action of GR/ligand on IL-8 gene promoter. Proteomics data showed beta-2 microglobulin, TNFSF15, TSH, CST3, NBL1 to show time-related decreases with prednisone, while CXCL13 showed increases, although these require validation. In summary, a single low dose of prednisone leads to broad suppression of the adrenal axis within 3 h, and down-regulation of inflammatory serum proteins by 6 h.