RETINOIC ACID INHIBITS BASAL AND INTERFERON-GAMMA -INDUCED EXPRESSION OF INTERCELLULAR ADHESION MOLECULE 1 IN MONOCYTIC CELLS

Retinoic acid (RA) and 1,25-(OH)2-vitamin D3 (1,25-D3) induced U937 cell maturation into distinct monocytic phenotypes, as demonstrated by up-regulation of CD23 by BA and CD14 by 1,25-D3. Differentiation by RA but not by 1,25-D3 was associated with reduction of basal and complete suppression of interferon-y (IFN-'y)- stimulated intercellular adhesion molecule 1 (ICAM-1) expression. Induction of cyclooxygenase activity by RA and attenuation of basal ICAM-1 expression exhibited similar kinetics. Treatment with indomethacin prevented and prostaglandin E2 (PGE2), dibutyryl-cAMP, or forskolin mimicked reduction of basal ICAM-1 expression by RA, indicating that this effect of RA is mediated by PGE2 syn- thesis and subsequent cAMP elevation. In contrast, sup- pression of IFN-y-induced ICAM-1 expression by RA was only partly reversible by indomethacin, suggesting that inhibition of IFN-'y stimulation was not completely due to cyclooxygenase induction. RA did not always counter- act IFN-'y, as it cooperated with IFN-y in down- regulating very late activation antigen 4. Specific poly- merase chain reaction and Northern blotting of ICAM-1 mRNA revealed that RA suppressed ICAM-1 induction by IFN-y at the transcriptional level. RA also blocked ICAM-1 induction by IFN-y in isolated human blood monocytes. In conclusion, inhibition of basal and stimu- lated ICAM-1 expression in monocytic cells may provide a mechanism for beneficial anti-inflammatory effects of retinoids. J. Leukoc. Biol. 57: 401-406; 1995.