Molecular mechanisms involved in the estrogen-dependent regulation of calcineurin in systemic lupus erythematosus T cells

Previous experiments in our laboratory indicated that calcineurin expressio n and PP2B phosphatase activity increased when estrogen was cultured with S LE T cells but not with T cells from normal women. In this report we extend ed our findings to show that estrogen receptor (ER) antagonism by ICI 182,7 80 inhibited the estrogen dependent increase in calcineurin mRNA and phosph atase PP2B activity indicating that estrogen action was mediated through th e ER. Inhibition of de novo protein synthesis with cycloheximide suggested that the estrogen-dependent increase in T cell calcineurin mRNA was a direc t effect of the ER and new protein synthesis was not required. Estrogen inc reased calcineurin mRNA in systemic lupus erythematosus (SLE) T cells at 6 h after the start of culture correlating with increased phosphatase activit y at this same time. Phosphatase activity increased significantly (P < 0.02 ) in lupus T cells cultured for 8 h in estradiol containing medium. Reverse transcription and polymerase chain amplification revealed that ER-beta and ER-alpha were expressed in female and male T cells from SLE patients and n ormal controls. However, calcineurin steady-state mRNA levels were unaffect ed by estradiol in cultured T cells from male SLE patients and normal male and female controls. These data indicate that estrogen, bound to the ER, ev okes a direct increase in calcineurin expression in T cells from female lup us patients. This gender-specific response suggests that ER function is alt ered in women with the female predominant autoimmune disease, SLE. (C) 2000 Academic Press.