Prostaglandin E2 mediates growth arrest in NFS-60 cells by down-regulating interleukin-6 receptor expression

Abstract

Interleukin-6 (IL-6), a potent myeloid mitogen, and the immunosuppressive prostanoid prostaglandin E2 (PGE2) are elevated following thermal injury and sepsis. We have previously demonstrated that bone marrow myeloid commitment shifts toward monocytopoiesis and away from granulocytopoiesis during thermal injury and sepsis and that PGE2 plays a central role in this alteration. Here we investigated whether PGE2 can modulate IL-6-stimulated growth in the promyelocytic cell line, NFS-60, by down-regulating IL-6 receptor (IL-6r) expression. Exposure of NFS-60 cells to PGE2 suppressed IL-6-stimulated proliferation as well as IL-6r expression. Receptor down-regulation is functionally significant since IL-6-induced signal transduction through activators of transcription (STAT)-3 is also decreased. Down-regulation of IL-6r correlated with the ability of PGE2 to arrest cells in the G0/G1 phase of the cell cycle. PGE2 appears to signal through EP2 receptors. Butaprost (EP2 agonist) but not sulprostone (EP3 agonist) inhibited IL-6-stimulated proliferation. In addition, an EP2 antagonist (AH6809) alleviated the anti-proliferative effects of PGE2. NFS-60 cells express predominantly EP2 and EP4 receptors. While PGE2 down-regulated both the IL-6r protein and mRNA expression, it had no influence on EP2 or EP4 mRNA expression. The present study demonstrates that PGE2 is a potent down-regulator of IL-6r expression and thus may provide a mechanistic explanation for the granulocytopenia seen in thermal injury and sepsis.

Prostaglandin E2 Augments IL-10 Signaling and Function

“…We were surprised to find that PGE 2 augments IL-10-induced STAT3 phosphorylation and gene expression because previous studies demonstrated that PGE 2 and cAMP usually inhibit cytokine-induced STAT activation (9,10,28). To our knowledge, these data are the first demonstration that PGE 2 augments IL-10 signaling and function.…”

“…We suggest that increased cAMP production and subsequent activation of PKA are a possible mechanism by which PGE 2 modulates IL-10 signaling. PGE 2 augments or inhibits IL-6-induced STAT3 activation according to cell type (10,11). In PIN cells, PGE 2 stimulates soluble IL-6R release, STAT3 phosphorylation, and DNA binding activity.…”

“…PGE 2 has been shown to inhibit STAT1 DNA binding activity in mononuclear cells and to inhibit IL-6-induced STAT activation in NFS-60 cells (9,10). We began the present study by examining whether PGE 2 modulates cytokine-induced STAT activation in THP-1 cells.…”

“…Activators of the cAMP signaling pathway, such as PGE 2 , inhibit STAT1 DNA binding activity in mononuclear cells (9), and also inhibit IL-6-induced STAT activation in NFS-60 cells (10). In addition, PGE 2 activates IL-6 signaling via stimulation of the soluble IL-6R release in prostatic intraepithelial neoplasia (PIN) cells (11).…”

A Role for Stroma-Derived Annexin A1 as Mediator in the Control of Genetic Susceptibility to T-Cell Lymphoblastic Malignancies through Prostaglandin E2 Secretion

“…4B). Because it had been suggested that PGE 2 might also interfere in the process of lymphoid cells by mediating growth arrest (27), we also explored this possibility by determining the number of thymocytes at different phases of the cell cycle. Compared with the control, PGE 2 -treated primary thymocytes did not show changes in cell cycle distribution, but they did exhibit statistically significant increases in the number of cells at the sub-G 1 region in a dosedependent manner (Fig.…”