EP4 EP2 RECEPTOR-SPECIFIC PROSTAGLANDIN E-2 REGULATION OF INTERLEUKIN-6 GENERATION BY HUMAN HSB.2 EARLY T-CELLS/

Human leukemic early T cells of the HSB.2 line coexpress the EP2, EP3 and EP4 subtypes of prostaglandin E-2 (PGE(2)) receptors (Rs). EP, Rs have previously been demonstrated to transduce PGE, stimulation of sec retion of matrix metalloproteinase (MMP)-9 by HSB.2 T cells through Ca ++-dependent enhancement of MMP-9 mRNA transcription. We now show that PGE(2) and the EP4/EP2/EP3 R-selective agonist misoprostol, but not t he EP3 R-directed agonists sulprostone and M&B28767, induced increases in HSB.2 T cell interleukin-6 (IL-6) mRNA and secretion. Pharmacologi cal agents that increase intracellular concentration of cyclic AMP ([c AMP](i)) mimicked and synergistically enhanced induction of IL-6 secre tion by PGE(2), whereas inhibitors of protein kinase A (PKA) but not p rotein kinase C suppressed PGE(2)-evoked increases in IL-6 secretion, suggesting that cAMP and PKA are the intracellular messengers of the P GE(2) effect. Exposure of HSB.2 T cells to the mitogenic lectin concan avalin A (Con A) increased basal IL-6 secretion, without a change in I L-6 mRNA level. Con A-stimulated HSB.2 T cells responded to PGE, with greater increases in IL-6 mRNA and secretion of IL-6. Con A also down- regulated mRNA encoding both EP3 Rs and EP2 Rs, and concurrently up-re gulated mRNA encoding EP4 Rs of HSB.2 T cells. Therefore, EP4 and EP2 Rs mediate PGE(2)-induced increases in IL-6 secretion by HSB.2 T cells through a transcriptional and cAMP dependent-mechanism. The increased ratio of EP4 Rs/EP3 Rs may contribute to Con A enhancement of PGE(2)- elicited increases in IL-6 secretion by HSB.2 T cells.