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.
Footnotes
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Send reprint requests to: Edward J. Goetzl, M.D., Department of Medicine, University of California, Box 0711, 533 Parnassus, San Francisco, CA 94143-0711.
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↵1 This research was supported by Grant HL31809 from the National Institutes of Health. L.Z. is supported by a Postdoctoral Research Training Fellowship of the American Lung Association. S.A. is an Arthritis Investigator of the Arthritis Foundation.
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Received February 26, 1998.
- Abbreviations:
- PGE2
- prostaglandin E2
- R
- receptor
- AC
- adenylyl cyclase
- [cAMP]i
- intracellular concentration of cyclic AMP
- IBMX
- 3-isobutyl-1-methylxanthine
- FBS
- fetal bovine serum
- HBSS
- Hanks’ balanced salt solution
- RT-PCR
- reverse transcription-polymerase chain reaction
- IL
- interleukin
- Accepted May 8, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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