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 D-3 (1,25-D-3) induced U93 7 cell maturation into distinct monocytic phenotypes, as demonstrated by up-regulation of CD23 by RA and CD14 by 1,25-D-3. Differentiation b y RA but not by 1,25-D-3 was associated with reduction of basal and co mplete suppression of interferon-gamma (IFN-gamma)-stimulated intercel lular adhesion molecule 1 (ICAM-1) expression. Induction of cyclooxyge nase activity by RA and attenuation of basal ICAM-1 expression exhibit ed similar kinetics. Treatment with indomethacin prevented and prostag landin E(2) (PGE(2)), dibutyryl-cAMP, or forskolin mimicked reduction of basal ICAM-1 expression by RA, indicating that this effect of RA is mediated by PGE(2) synthesis and subsequent cAMP elevation. In contra st, suppression of IFN-gamma-induced ICAM-1 expression by RA was only partly reversible by indomethacin, suggesting that inhibition of IFN-g amma stimulation was not completely due to cyclooxygenase induction. R A did not always counteract IFN-gamma, as it cooperated with IFN-gamma in downregulating very late activation antigen 4. Specific polymerase chain reaction and Northern blotting of ICAM-1 mRNA revealed that RA suppressed ICAM-1 induction by IFN-gamma at the transcriptional level. RA also blocked ICAM-1 induction by IFN-gamma in isolated human blood monocytes. In conclusion, inhibition of basal and stimulated ICAM-1 e xpression in monocytic cells may provide a mechanism for beneficial an ti-inflammatory effects of retinoids.