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
SN - 1360-8185
VL - 11
SP - 2159
EP - 2165
JO - Apoptosis
JF - Apoptosis
IS - 12
ER -