Abstract

Human leukemic early T cells of the HSB.2 line coexpress the EP₂, EP₃ and EP₄ subtypes of prostaglandin E₂ (PGE₂) receptors (Rs). EP₃ Rs have previously been demonstrated to transduce PGE₂ stimulation of secretion of matrix metalloproteinase (MMP)-9 by HSB.2 T cells through Ca⁺⁺-dependent enhancement of MMP-9 mRNA transcription. We now show that PGE₂ and the EP₄/EP₂/EP₃ R-selective agonist misoprostol, but not the EP₃ R-directed agonists sulprostone and M&B28767, induced increases in HSB.2 T cell interleukin-6 (IL-6) mRNA and secretion. Pharmacological agents that increase intracellular concentration of cyclic AMP ([cAMP]_i) mimicked and synergistically enhanced induction of IL-6 secretion by PGE₂, whereas inhibitors of protein kinase A (PKA) but not protein kinase C suppressed PGE₂-evoked increases in IL-6 secretion, suggesting that cAMP and PKA are the intracellular messengers of the PGE₂effect. Exposure of HSB.2 T cells to the mitogenic lectin concanavalin A (Con A) increased basal IL-6 secretion, without a change in IL-6 mRNA level. Con A-stimulated HSB.2 T cells responded to PGE₂with 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-regulated mRNA encoding EP₄ Rs of HSB.2 T cells. Therefore, EP₄ and EP₂ Rs mediate PGE₂-induced increases in IL-6 secretion by HSB.2 T cells through a transcriptional and cAMP dependent-mechanism. The increased ratio of EP₄Rs/EP₃ Rs may contribute to Con A enhancement of PGE₂-elicited increases in IL-6 secretion by HSB.2 T cells.