Molecular mechanisms involved in the estrogen-dependent regulation of calcineurin in systemic lupus erythematosus T cells.
Previous experiments in our laboratory indicated that calcineurin expression and PP2B phosphatase activity increased when estrogen was cultured with SLE T cells but not with T cells from normal women. In this report we extended our findings to show that estrogen receptor (ER) antagonism by ICI 182,780 inhibited the estrogen-dependent increase in calcineurin mRNA and phosphatase PP2B activity indicating that estrogen action was mediated through the ER. Inhibition of de novo protein synthesis with cycloheximide suggested that the estrogen-dependent increase in T cell calcineurin mRNA was a direct effect of the ER and new protein synthesis was not required. Estrogen increased calcineurin mRNA in systemic lupus erythematosus (SLE) T cells at 6 h after the start of culture correlating with increased phosphatase activity 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 normal controls. However, calcineurin steady-state mRNA levels were unaffected 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, evokes a direct increase in calcineurin expression in T cells from female lupus patients. This gender-specific response suggests that ER function is altered in women with the female predominant autoimmune disease, SLE.
Rider
V
V
Division of Molecular Biology and Biochemistry, School of Biological Sciences, Kansas City, Missouri 64110, USA.
Jones
S R
SR
Evans
M
M
Abdou
N I
NI
D000293:Adolescent; D000328:Adult; D019703:Calcineurin / Q000235:genetics*; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011287:Prejudice; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000502:physiology; D013601:T-Lymphocytes / Q000737:chemistry / Q000378:metabolism
D004967:Estrogens; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D004958:Estradiol; D019703:Calcineurin