TY - JOUR
T1 - Selenoprotein-dependent up-regulation of hematopoietic prostaglandin D 2 synthase in macrophages is mediated through the activation of Peroxisome Proliferator-activated Receptor (PPAR) γ
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
PY - 2011/8/5
Y1 - 2011/8/5
N2 - 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.
AB - 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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U2 - 10.1074/jbc.M111.260547
DO - 10.1074/jbc.M111.260547
M3 - Article
C2 - 21669866
AN - SCOPUS:79961014471
SN - 0021-9258
VL - 286
SP - 27471
EP - 27482
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 31
ER -