Functional antagonism between IL-2 and PGA1 or PGJ2 in the control of proliferation of human cord blood-derived mononuclear cells.
Cyclopentenone prostaglandins PGA1 and PGJ2 induce growth arrest at the G1/S interphase of the cell cycle in tumour cell lines. Notably, 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 PGA1/PGJ2-dependent growth inhibition of IL-2-stimulated primary human cord blood mononuclear cells (CBMCs) was found to be mediated by interference with the IL-2 proliferative signal. Both prostaglandins (PGs) inhibited the synthesis of total RNA and protein in IL-2 stimulated cells. PGA1 and even more PGJ2 downregulated the expression of IL-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 spontaneously. Cyclin A/Cdk2 complexes regulate G1/S transition during the cell cycle. In IL-2-stimulated cells, the levels of Cdk2 were found to be lower in PG-treated cells than those detected in controls. In conclusion, cyclopentenone PGs inhibit CBMCs spontaneous or IL-2-dependent proliferation in part by interfering with the IL-2 pathway.
Franzese
O
O
Department of Experimental Medicine and Biochemical Sciences, University of Rome, Italy.
Bonmassar
E
E
Marcucci
A
A
D'Onofrio
C
C
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D005312:Fetal Blood; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear; D011247:Pregnancy; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011454:Prostaglandins A / Q000494:pharmacology*; D014176:Protein Biosynthesis; D012313:RNA / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014529:Uridine / Q000378:metabolism
D000970:Antineoplastic Agents; D007376:Interleukin-2; D011454:Prostaglandins A; D011994:Recombinant Proteins; C037112:9-deoxy-delta-9-prostaglandin D2; D012313:RNA; D015230:Prostaglandin D2; D014529:Uridine