Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-alpha and interferon-gamma, and has potential in the treatment of arthritis

Abstract

Evidence suggests that spironolactone, an aldosterone antagonist, has effects on many cell types independent of its binding to cytosolic mineralocorticoid receptors. We tested the effects of spironolactone on ex vivo-activated human blood leucocytes using gene expression analyses (GeneChip, 12,000 genes) and enzyme immunoassay for quantitating secreted pro- and anti-inflammatory cytokines. Furthermore, to evaluate the safety and efficacy of spironolactone as an anti-inflammatory drug 21 patients with rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) or other arthritides were treated for up to 22 months with 1-3 mg/kg/day. Spironolactone, at in vivo attainable doses, markedly suppressed transcription of several proinflammatory cytokines and, accordingly, inhibited release of tumour necrosis factor, lymphotoxin, interferon-gamma, granulocyte-macrophage colony-stimulating factor and interleukin 6 (70-90% inhibition). Release of these cytokines was also suppressed when testing whole blood from RA patients receiving 50 mg spironolactone twice daily, indicating that pharmaceutical use of the drug may suppress the release of inflammatory cytokines. Spironolactone therapy was generally well tolerated, although treatment had to be stopped in two adults on concomitant methotrexate therapy. Sixteen patients (76%) responded favourably. American College of Rheumatology criteria (ACR)20 or better was achieved in six of nine RA patients; four reached ACR70. Eight of nine JIA patients improved. In conclusion, spironolactone inhibits production of several proinflammatory cytokines considered to be of pathogenic importance in many immunoinflammatory diseases and shows positive effect in patients with chronic arthritis. Its effect as an anti-inflammatory drug should be explored, because prolonged spironolactone therapy is reasonably safe and economically attractive compared with many modern anti-inflammatory therapies.

Fig. 1

Effect of spironolactone on whole-blood cytokine production. Human whole blood was diluted to 20% v/v with medium RPMI-1640 and incubated with drugs, or with medium alone. After 22 h, the supernatants were isolated and tested by ELISA for cytokines. Results are shown as percentage of controls cultured in parallel with PHA + LPS, but without drug (mean ± s.e.m., n = 6). Asterixes mark values significantly different from those of controls (*P < 0·05 and **P < 0·01, Student's t-test). The levels of cytokines in the controls were IL-1α: 348 ± 128, IL-1β: 2588 ± 1019, TNF: 1063 ± 201, LT-α: 592 ± 228, IFN-γ: 2550 ± 357, GM-CSF: 2175 ± 685, IL-6: 10 490 ± 2737, IL-10: 97 ± 24 (pg/ml, mean ± s.e.m., n = 6).