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.
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February 2003
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Research Article|
February 15 2003
Prostaglandin E2 mediates growth arrest in NFS-60 cells by down-regulating interleukin-6 receptor expression
Kumudika I. de SILVA;
Kumudika I. de SILVA
Burn and Shock Trauma Institute, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, U.S.A.
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Asif N. DAUD;
Asif N. DAUD
Burn and Shock Trauma Institute, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, U.S.A.
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JiangPing DENG;
JiangPing DENG
Burn and Shock Trauma Institute, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, U.S.A.
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Stephen B. JONES;
Stephen B. JONES
Burn and Shock Trauma Institute, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, U.S.A.
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Richard L. GAMELLI;
Richard L. GAMELLI
Burn and Shock Trauma Institute, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, U.S.A.
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Ravi SHANKAR
Ravi SHANKAR
1
Burn and Shock Trauma Institute, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, U.S.A.
1To whom correspondence should be addressed (e-mail rshanka@bsd.lumc.edu).
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Publisher: Portland Press Ltd
Received:
September 27 2002
Revision Received:
November 07 2002
Accepted:
November 12 2002
Accepted Manuscript online:
November 12 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 370 (1): 315–321.
Article history
Received:
September 27 2002
Revision Received:
November 07 2002
Accepted:
November 12 2002
Accepted Manuscript online:
November 12 2002
Citation
Kumudika I. de SILVA, Asif N. DAUD, JiangPing DENG, Stephen B. JONES, Richard L. GAMELLI, Ravi SHANKAR; Prostaglandin E2 mediates growth arrest in NFS-60 cells by down-regulating interleukin-6 receptor expression. Biochem J 15 February 2003; 370 (1): 315–321. doi: https://doi.org/10.1042/bj20021512
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