Retinoic Acid Inhibits CD40 1 Interleukin-4–Mediated IgE Production In Vitro

To elucidate the role of retinoic acid (RA) in anti-CD40 1 interleukin-4 (IL-4)–mediated B-cell activation, the effect of 10212 to 1026 mol/L RA was studied in anti-CD40 (1 mg/mL) 1 IL-4 (5 ng/mL)-mediated proliferation and Ig synthesis by human peripheral blood mononuclear cells (PBMC) and B cells in healthy donors. Anti-CD40 1 IL-4–mediated proliferation of PBMC and B cells was inhibited by RA in a dosedependent manner, with maximal inhibition of 62% 6 5% in PBMC and 55% 6 4.4% in B cells by all-trans RA, and 58% 6 6.7% and 51% 6 4.7%, respectively by 13-cis RA. IgE synthesis was even more markedly inhibited by RA starting at concentrations of G10214 mol/L for B cells and G10210 mol/L for PBMC. Maximal inhibition of IgE production for B cells was at 1028 mol/L for all-trans RA (94% 6 1.8%) and 96% 6 3.2% for 13-cis RA. Low concentrations of RA inhibiting IgE synthesis (10210 mol/L) affected neither B-cell proliferation nor the production of IgA, IgG, and IgM. Elucidation of the mechanism involved in this inhibition of IgE production shows that epsilon germline transcription is decreased by RA, whereas production of interferon-g (IFN-g) was not enhanced in the presence of RA. To differentiate whether the RA effect was mediated by RA receptors a, b, and g, the expression of the retinoic acid receptors (RAR) was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). The data show that unstimulated human peripheral B cells express mRNA of the RA receptor a, b, and g. Using retinoids with different receptor binding specificity (CD336, CD437, CD2019, CD367), dose-dependent inhibition of IgE synthesis was shown by all four derivates, but was most marked by an RA binding the a receptor with high specificity. Taken together, this study shows that RA inhibits IgE production of anti-CD40 1 IL-4–stimulated B cells in vitro. r 1998 by The American Society of Hematology.