FUNCTIONAL ANTAGONISM BETWEEN IL-2 AND PGA(1) OR PGJ(2) IN THE CONTROL OF PROLIFERATION OF HUMAN CORD BLOOD-DERIVED MONONUCLEAR-CELLS

Cyclopentenone prostaglandins PGA(1) and PGJ(2) induce growth arrest a t the G(1)/S interphase of the cell cycle in tumour cell lines. Notabl y, PGE, the precursor molecule of PGA, downregulates the interleukin ( IL)-2-dependent proliferation of lymphocytes. Therefore the IL-2/IL-2 receptor system and relative signal transduction is a possible target of the antiproliferative effect of PGA/PGJ. In the present study the P GA(1)/PGJ(2)-dependent growth inhibition of IL-2-stimulaled primary hu man cord blood mononuclear cells (CBMCs) was found to be mediated by i nterference with the IL-2 proliferative signal. Both prostaglandins (P Gs) inhibited the synthesis of total RNA and protein in IL-2 stimulate d cells. PGA(1) and even more PGJ(2) downregulated the expression of I L-2 receptor alpha (CD25 phenotype). IL-2 partly reversed this effect. Moreover, suppression of IL-2-stimulated cells was not the result of PG-mediated activation of apoptosis. On the contrary, PGs reduced both apoptosis and the high expression of c-Jun detectable in CBMCs sponta neously. Cyclin A/Cdk2 complexes regulate G(1)/S transition during the cell cycle. In IL-2-stimulated cells, the levels of Cdk2 were found t o be lower in PG-treated cells than those detected in controls. In con clusion, cyclopentenone PGs inhibit CBMCs spontaneous or IL-2-dependen t proliferation in part by interfering with the IL-2 pathway. (C) 1997 International Society for Immunopharmacology.