Selenoprotein-dependent up-regulation of hematopoietic prostaglandin D 2 synthase in macrophages is mediated through the activation of Peroxisome Proliferator-activated Receptor (PPAR) γ

Ujjawal H. Gandhi, Naveen Kaushal, Kodihalli C. Ravindra, Shailaja Hegde, Shakira M. Nelson, Vivek Narayan, Hema Vunta, Robert F. Paulson, K. Sandeep Prabhu

Research output: Contribution to journalArticle

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Abstract

The plasticity of macrophages is evident from their dual role in inflammation and resolution of inflammation that are accompanied by changes in the transcriptome and metabolome. Along these lines, we have previously demonstrated that the micronutrient selenium increases macrophage production of arachidonic acid (AA)-derived anti-inflammatory 15-deoxy-Δ 12,14-prostaglandin J 2 (15d-PGJ 2) and decreases the proinflammatory PGE 2. Here, we hypothesized that selenium modulated the metabolism of AA by a differential regulation of various prostaglandin (PG) synthases favoring the production of PGD 2 metabolites, Δ12-PGJ 2 and 15d-PGJ 2. A dose-dependent increase in the expression of hematopoietic-PGD 2 synthase (H-PGDS) by selenium and a corresponding increase in Δ12-PGJ 2 and 15d-PGJ 2 in RAW264.7 macrophages and primary bone marrow-derived macrophages was observed. Studies with organic non-bioavailable forms of selenium and the genetic manipulation of cellular selenium incorporation machinery indicated that selenoproteins were necessary for H-PGDS expression and 15d-PGJ 2 production. Treatment of selenium-deficient macrophages with rosiglitazone, a peroxisome proliferator-activated receptor γ ligand, up-regulated H-PGDS. Furthermore, electrophoretic mobility shift assays indicated the presence of an active peroxisome proliferator-activated receptor-response element in murine Hpgds promoter suggesting a positive feedback mechanism of H-PGDS expression. Alternatively, the expression of nuclear factor-κB-dependent thromboxane synthase and microsomal PGE 2 synthase was down-regulated by selenium. Using a Friend virus infection model of murine leukemia, the onset of leukemia was observed only in selenium-deficient and indomethacin-treated selenium-supplemented mice but not in the selenium-supplemented group or those treated with 15d-PGJ 2. These results suggest the importance of selenium in the shunting of AA metabolism toward the production of PGD 2metabolites, which may have clinical implications.

Original languageEnglish (US)
Pages (from-to)27471-27482
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number31
DOIs
StatePublished - Aug 5 2011

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prostaglandin R2 D-isomerase
Selenoproteins
Prostaglandins D
Peroxisome Proliferator-Activated Receptors
Macrophages
Selenium
Up-Regulation
Chemical activation
Prostaglandins
Arachidonic Acid
rosiglitazone
Prostaglandins E
Metabolism
Leukemia
Friend murine leukemia virus
Inflammation
Electrophoretic mobility
Metabolome

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Gandhi, Ujjawal H. ; Kaushal, Naveen ; Ravindra, Kodihalli C. ; Hegde, Shailaja ; Nelson, Shakira M. ; Narayan, Vivek ; Vunta, Hema ; Paulson, Robert F. ; Prabhu, K. Sandeep. / Selenoprotein-dependent up-regulation of hematopoietic prostaglandin D 2 synthase in macrophages is mediated through the activation of Peroxisome Proliferator-activated Receptor (PPAR) γ. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 31. pp. 27471-27482.
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abstract = "The plasticity of macrophages is evident from their dual role in inflammation and resolution of inflammation that are accompanied by changes in the transcriptome and metabolome. Along these lines, we have previously demonstrated that the micronutrient selenium increases macrophage production of arachidonic acid (AA)-derived anti-inflammatory 15-deoxy-Δ 12,14-prostaglandin J 2 (15d-PGJ 2) and decreases the proinflammatory PGE 2. Here, we hypothesized that selenium modulated the metabolism of AA by a differential regulation of various prostaglandin (PG) synthases favoring the production of PGD 2 metabolites, Δ12-PGJ 2 and 15d-PGJ 2. A dose-dependent increase in the expression of hematopoietic-PGD 2 synthase (H-PGDS) by selenium and a corresponding increase in Δ12-PGJ 2 and 15d-PGJ 2 in RAW264.7 macrophages and primary bone marrow-derived macrophages was observed. Studies with organic non-bioavailable forms of selenium and the genetic manipulation of cellular selenium incorporation machinery indicated that selenoproteins were necessary for H-PGDS expression and 15d-PGJ 2 production. Treatment of selenium-deficient macrophages with rosiglitazone, a peroxisome proliferator-activated receptor γ ligand, up-regulated H-PGDS. Furthermore, electrophoretic mobility shift assays indicated the presence of an active peroxisome proliferator-activated receptor-response element in murine Hpgds promoter suggesting a positive feedback mechanism of H-PGDS expression. Alternatively, the expression of nuclear factor-κB-dependent thromboxane synthase and microsomal PGE 2 synthase was down-regulated by selenium. Using a Friend virus infection model of murine leukemia, the onset of leukemia was observed only in selenium-deficient and indomethacin-treated selenium-supplemented mice but not in the selenium-supplemented group or those treated with 15d-PGJ 2. These results suggest the importance of selenium in the shunting of AA metabolism toward the production of PGD 2metabolites, which may have clinical implications.",
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Selenoprotein-dependent up-regulation of hematopoietic prostaglandin D 2 synthase in macrophages is mediated through the activation of Peroxisome Proliferator-activated Receptor (PPAR) γ. / Gandhi, Ujjawal H.; Kaushal, Naveen; Ravindra, Kodihalli C.; Hegde, Shailaja; Nelson, Shakira M.; Narayan, Vivek; Vunta, Hema; Paulson, Robert F.; Prabhu, K. Sandeep.

In: Journal of Biological Chemistry, Vol. 286, No. 31, 05.08.2011, p. 27471-27482.

Research output: Contribution to journalArticle

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AU - Gandhi, Ujjawal H.

AU - Kaushal, Naveen

AU - Ravindra, Kodihalli C.

AU - Hegde, Shailaja

AU - Nelson, Shakira M.

AU - Narayan, Vivek

AU - Vunta, Hema

AU - Paulson, Robert F.

AU - Prabhu, K. Sandeep

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