TY - JOUR

T1 - Spironolactone induces apoptosis and inhibits NF-kappaB independent of the mineralocorticoid receptor

AU - Sønder, Søren Ulrik Salling

AU - Woetmann, Anders

AU - Odum, Niels

AU - Bendtzen, Klaus

N1 - Keywords: Aldosterone Antagonists; Apoptosis; Caspase 3; Cytokines; Humans; I-kappa B Proteins; Leukocytes, Mononuclear; NF-kappa B; Phosphorylation; Receptors, Mineralocorticoid; Spironolactone; Sulfasalazine

PY - 2006

Y1 - 2006

N2 - Spironolactone (SPIR) binds to cytoplasmic mineralocorticoid receptors (MR) and functions as an aldosterone (ALDO) antagonist. Recently, however, the drug was shown to have an early MR independent, suppressive effect on immunoactive and inflammatory cytokines as well as an apoptotic effect on blood mononuclear cells (MNC). To elucidate the mechanism behind SPIR's apoptotic effect, we investigated the relation between apoptosis and cytokine suppression for SPIR along with the apoptosis-inducing and antiinflammatory drug sulfasalazine (SFZ). Using human MNC, we found that SPIR and SFZ, at concentrations 10 and 1000 muM, respectively, significantly increased both apoptosis and cell death. Production of inflammatory cytokines was significantly reduced by 3 to 30 muM SPIR and by 300 to 1000 muM SFZ. We also found that 0.4 muM SPIR and 300 muM SFZ significantly reduced the activity of NF-kappaB, a transcription factor involved in both apoptosis and immunoinflammation. ALDO, the MR antagonist, eplerenone, and the SPIR metabolite, 7alpha-thiomethyl-spironolactone, slightly reduced NF-kappaB activity, but they did not interfere with SPIR's effect, showing that MR binding is not involved in SPIR-induced suppression of NF-kappaB activity. Finally, phosphorylation of IkappaBalpha was also significantly reduced by SPIR. These results provide new insight into the apoptotic and anti-inflammatory effects of SPIR.

AB - Spironolactone (SPIR) binds to cytoplasmic mineralocorticoid receptors (MR) and functions as an aldosterone (ALDO) antagonist. Recently, however, the drug was shown to have an early MR independent, suppressive effect on immunoactive and inflammatory cytokines as well as an apoptotic effect on blood mononuclear cells (MNC). To elucidate the mechanism behind SPIR's apoptotic effect, we investigated the relation between apoptosis and cytokine suppression for SPIR along with the apoptosis-inducing and antiinflammatory drug sulfasalazine (SFZ). Using human MNC, we found that SPIR and SFZ, at concentrations 10 and 1000 muM, respectively, significantly increased both apoptosis and cell death. Production of inflammatory cytokines was significantly reduced by 3 to 30 muM SPIR and by 300 to 1000 muM SFZ. We also found that 0.4 muM SPIR and 300 muM SFZ significantly reduced the activity of NF-kappaB, a transcription factor involved in both apoptosis and immunoinflammation. ALDO, the MR antagonist, eplerenone, and the SPIR metabolite, 7alpha-thiomethyl-spironolactone, slightly reduced NF-kappaB activity, but they did not interfere with SPIR's effect, showing that MR binding is not involved in SPIR-induced suppression of NF-kappaB activity. Finally, phosphorylation of IkappaBalpha was also significantly reduced by SPIR. These results provide new insight into the apoptotic and anti-inflammatory effects of SPIR.

U2 - 10.1007/s10495-006-0286-3

DO - 10.1007/s10495-006-0286-3

M3 - Journal article

C2 - 17051331

VL - 11

SP - 2159

EP - 2165

JO - Apoptosis : an international journal on programmed cell death

JF - Apoptosis : an international journal on programmed cell death

SN - 1360-8185

IS - 12

ER -