title: Corticosteroid induction of Ig+Ia- B cells in vitro is mediated via interaction with the glucocorticoid cytoplasmic receptor.
abstract: Flow microfluorometry was used to examine the effect of dexamethasone on the expression of surface Ia (sIa) on resting and activated murine B cells. Although dexamethasone resulted in a 50% reduction in sIa expression 12 h after injection, it was significantly less suppressive when injected together with B cell activators. In vitro dexamethasone, but not other related steroid hormones, induced a population of cells that were sIg+sIa-. A 20% reduction in the expression of sIa was noted by 4 h of culture with 10 nM dexamethasone, but maximal inhibition of 70% was not reached until 12 h of culture, and this degree of suppression persisted as long as dexamethasone remained in culture. When the dexamethasone was washed out after 8 h of culture, the maximal reduction was still noted at 12 h, but by 24 h there was re-expression of sIa toward base line levels, indicating it did not induce irreversible lethal alterations in the B cell. The inhibition of sIa expression correlated with a specific reduction in the quantity of messenger RNA for sIa as measured by Northern blot analysis, indicating that this is mediated at least in part by suppression of the steady state levels of Ia mRNA. The corticosteroid receptor antagonist RU486 was able to reverse the suppressive effects of dexamethasone on sIa expression, thus demonstrating that its effect is mediated specifically by binding to its intracellular receptor. Furthermore, when protein synthesis was inhibited during the short period of time that cells were preincubated with dexamethasone, minimal suppression of Ia expression was noted, suggesting that the dexamethasone may be stimulating a protein that has suppressive effects on MHC class II expression. The suppressive effects of dexamethasone in vitro were substantially reduced when B cells were simultaneously activated by stimuli that increase the expression of sIa. These data indicate that the suppressive effects of corticosteroids on immune response Ag are corticosteroid specific; are greater in resting than in activated B cells; are induced via the classical steroid mechanism of action, which is receptor mediated; and may result from the induction of an inhibitory protein that suppresses Ia mRNA.
authors.affiliation: Department of Medicine, Walter Reed Army Medical Center, Washington, DC 20307.
authors.forename: V M
authors.initials: VM
authors.lastname: McMillan
authors.forename: G J
authors.initials: GJ
authors.lastname: Dennis
authors.forename: L H
authors.initials: LH
authors.lastname: Glimcher
authors.forename: F D
authors.initials: FD
authors.lastname: Finkelman
authors.forename: J J
authors.initials: JJ
authors.lastname: Mond
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D003907:Dexamethasone / Q000494:pharmacology*; D004963:Estrenes / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D015735:Mifepristone; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis*; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology*
chemical_list: D004963:Estrenes; D000949:Histocompatibility Antigens Class II; D011947:Receptors, Antigen, B-Cell; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone