Glucocorticoid inhibition of activation-induced cytidine deaminase expression in human B lymphocytes.
We examined whether glucocorticoids could modulate the expression of activation-induced cytidine deaminase (AICDA), the principal regulator of the processes of immunoglobulin gene somatic hypermutation and class switch recombination in B lymphocytes. Treatment of human B cells with IL-4 and anti-CD40 antibody for 18-20h resulted in induction of expression of AICDA mRNA by over 10-fold. Dexamethasone at 10nM concentration inhibited AICDA induction by an average of 51.8% (p<0.0001). These effects of glucocorticoids were found to be dose dependent in the physiologic range and were reversible by co-treatment with a glucocorticoid receptor antagonist. Human B cell viability and proliferation were unaltered by glucocorticoid treatment. These data demonstrate that physiologic concentrations of glucocorticoids can act on human B lymphocytes through glucocorticoid receptor-mediated mechanisms to diminish the expression of AICDA, a key regulator of humoral immune responses.
Division of Endocrinology, Diabetes, and Metabolism, The Pennsylvania State University, College of Medicine, Milton S. Hershey Medical Center, Hershey, PA 17033, United States.
Ann L
AL
Benko
Division of Rheumatology, The Pennsylvania State University, College of Medicine, Milton S. Hershey Medical Center, Hershey, PA 17033, United States.
Nancy J
NJ
Olsen
Division of Endocrinology, Diabetes, and Metabolism, The Pennsylvania State University, College of Medicine, Milton S. Hershey Medical Center, Hershey, PA 17033, United States. Electronic address: wkovacs@hmc.psu.edu.
William J
WJ
Kovacs
D000906:Antibodies / Q000494:pharmacology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D019013:CD40 Antigens / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D003907:Dexamethasone / Q000494:pharmacology*; D004306:Dose-Response Relationship, Immunologic; D005938:Glucocorticoids / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D056724:Immunity, Humoral; D017578:Immunoglobulin Class Switching / Q000187:drug effects; D015847:Interleukin-4 / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D011995:Recombination, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D000906:Antibodies; D019013:CD40 Antigens; D005938:Glucocorticoids; D006727:Hormone Antagonists; C508598:IL4 protein, human; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015847:Interleukin-4; D015735:Mifepristone; D003907:Dexamethasone; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
Activation-induced cytidine deaminase; B Lymphocytes; Class switch recombination; Glucocorticoids; Somatic hypermutation