The anti-inflammatory effects of selenium are mediated through 15-deoxy-Δ12,14-prostaglandin J2 in macrophages

Hema Vunta, Faith Davis, Umamaheswari D. Palempalli, Deepa Bhat, Ryan J. Arner, Jerry T. Thompson, Devin G. Peterson, C. Channa Reddy, Kumble Sandeep Prabhu

Research output: Contribution to journalArticle

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Abstract

Selenium is an essential micronutrient that suppresses the redox-sensitive transcription factor NF-κB-dependent pro-inflammatory gene expression. To understand the molecular mechanisms underlying the anti-inflammatory property of selenium, we examined the activity of a key kinase of the NF-κB cascade, IκB-kinase β (IKKβ) subunit, as a function of cellular selenium status in murine primary bone marrow-derived macrophages and RAW264.7 macrophage-like cell line. In vitro kinase assays revealed that selenium supplementation decreased the activity of IKKβ in lipopolysaccharide (LPS)-treated macrophages. Stimulation by LPS of selenium-supplemented macrophages resulted in a time-dependent increase in 15-deoxy-Δ 12,14-prostaglandin J2 (15d-PGJ2) formation, an endogenous inhibitor of IKKβ activity. Further analysis revealed that inhibition of IKKβ activity in selenium-supplemented cells correlated with the Michael addition product of 15d-PGJ2 with Cys-179 of IKKβ, while the formation of such an adduct was significantly decreased in the selenium-deficient macrophages. In addition, anti-inflammatory activities of selenium were also mediated by the 15d-PGJ2-dependent activation of the peroxisome proliferator-activated nuclear receptor-γ in macrophages. Experiments using specific cyclooxygenase (COX) inhibitors and genetic knockdown approaches indicated that COX-1, and not the COX-2 pathway, was responsible for the increased synthesis of 15d-PGJ2 in selenium-supplemented macrophages. Taken together, our results suggest that selenium supplementation increases the production of 15d-PGJ2 as an adaptive response to protect cells against oxidative stress-induced pro-inflammatory gene expression. More specifically, modification of protein thiols by 15d-PGJ2 represents a previously undescribed code for redox regulation of gene expression by selenium.

Original languageEnglish (US)
Pages (from-to)17964-17973
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number25
DOIs
StatePublished - Jun 22 2007

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Macrophages
Selenium
Anti-Inflammatory Agents
Gene expression
Phosphotransferases
Oxidation-Reduction
Lipopolysaccharides
15-deoxy-delta(12,14)-prostaglandin J2
Peroxisome Proliferators
Gene Expression
Cyclooxygenase 1
Peroxisome Proliferator-Activated Receptors
Oxidative stress
Cyclooxygenase Inhibitors
Micronutrients
Gene Expression Regulation
Cyclooxygenase 2
Cytoplasmic and Nuclear Receptors
Sulfhydryl Compounds
Assays

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Vunta, Hema ; Davis, Faith ; Palempalli, Umamaheswari D. ; Bhat, Deepa ; Arner, Ryan J. ; Thompson, Jerry T. ; Peterson, Devin G. ; Reddy, C. Channa ; Prabhu, Kumble Sandeep. / The anti-inflammatory effects of selenium are mediated through 15-deoxy-Δ12,14-prostaglandin J2 in macrophages. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 25. pp. 17964-17973.
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title = "The anti-inflammatory effects of selenium are mediated through 15-deoxy-Δ12,14-prostaglandin J2 in macrophages",
abstract = "Selenium is an essential micronutrient that suppresses the redox-sensitive transcription factor NF-κB-dependent pro-inflammatory gene expression. To understand the molecular mechanisms underlying the anti-inflammatory property of selenium, we examined the activity of a key kinase of the NF-κB cascade, IκB-kinase β (IKKβ) subunit, as a function of cellular selenium status in murine primary bone marrow-derived macrophages and RAW264.7 macrophage-like cell line. In vitro kinase assays revealed that selenium supplementation decreased the activity of IKKβ in lipopolysaccharide (LPS)-treated macrophages. Stimulation by LPS of selenium-supplemented macrophages resulted in a time-dependent increase in 15-deoxy-Δ 12,14-prostaglandin J2 (15d-PGJ2) formation, an endogenous inhibitor of IKKβ activity. Further analysis revealed that inhibition of IKKβ activity in selenium-supplemented cells correlated with the Michael addition product of 15d-PGJ2 with Cys-179 of IKKβ, while the formation of such an adduct was significantly decreased in the selenium-deficient macrophages. In addition, anti-inflammatory activities of selenium were also mediated by the 15d-PGJ2-dependent activation of the peroxisome proliferator-activated nuclear receptor-γ in macrophages. Experiments using specific cyclooxygenase (COX) inhibitors and genetic knockdown approaches indicated that COX-1, and not the COX-2 pathway, was responsible for the increased synthesis of 15d-PGJ2 in selenium-supplemented macrophages. Taken together, our results suggest that selenium supplementation increases the production of 15d-PGJ2 as an adaptive response to protect cells against oxidative stress-induced pro-inflammatory gene expression. More specifically, modification of protein thiols by 15d-PGJ2 represents a previously undescribed code for redox regulation of gene expression by selenium.",
author = "Hema Vunta and Faith Davis and Palempalli, {Umamaheswari D.} and Deepa Bhat and Arner, {Ryan J.} and Thompson, {Jerry T.} and Peterson, {Devin G.} and Reddy, {C. Channa} and Prabhu, {Kumble Sandeep}",
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Vunta, H, Davis, F, Palempalli, UD, Bhat, D, Arner, RJ, Thompson, JT, Peterson, DG, Reddy, CC & Prabhu, KS 2007, 'The anti-inflammatory effects of selenium are mediated through 15-deoxy-Δ12,14-prostaglandin J2 in macrophages', Journal of Biological Chemistry, vol. 282, no. 25, pp. 17964-17973. https://doi.org/10.1074/jbc.M703075200

The anti-inflammatory effects of selenium are mediated through 15-deoxy-Δ12,14-prostaglandin J2 in macrophages. / Vunta, Hema; Davis, Faith; Palempalli, Umamaheswari D.; Bhat, Deepa; Arner, Ryan J.; Thompson, Jerry T.; Peterson, Devin G.; Reddy, C. Channa; Prabhu, Kumble Sandeep.

In: Journal of Biological Chemistry, Vol. 282, No. 25, 22.06.2007, p. 17964-17973.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The anti-inflammatory effects of selenium are mediated through 15-deoxy-Δ12,14-prostaglandin J2 in macrophages

AU - Vunta, Hema

AU - Davis, Faith

AU - Palempalli, Umamaheswari D.

AU - Bhat, Deepa

AU - Arner, Ryan J.

AU - Thompson, Jerry T.

AU - Peterson, Devin G.

AU - Reddy, C. Channa

AU - Prabhu, Kumble Sandeep

PY - 2007/6/22

Y1 - 2007/6/22

N2 - Selenium is an essential micronutrient that suppresses the redox-sensitive transcription factor NF-κB-dependent pro-inflammatory gene expression. To understand the molecular mechanisms underlying the anti-inflammatory property of selenium, we examined the activity of a key kinase of the NF-κB cascade, IκB-kinase β (IKKβ) subunit, as a function of cellular selenium status in murine primary bone marrow-derived macrophages and RAW264.7 macrophage-like cell line. In vitro kinase assays revealed that selenium supplementation decreased the activity of IKKβ in lipopolysaccharide (LPS)-treated macrophages. Stimulation by LPS of selenium-supplemented macrophages resulted in a time-dependent increase in 15-deoxy-Δ 12,14-prostaglandin J2 (15d-PGJ2) formation, an endogenous inhibitor of IKKβ activity. Further analysis revealed that inhibition of IKKβ activity in selenium-supplemented cells correlated with the Michael addition product of 15d-PGJ2 with Cys-179 of IKKβ, while the formation of such an adduct was significantly decreased in the selenium-deficient macrophages. In addition, anti-inflammatory activities of selenium were also mediated by the 15d-PGJ2-dependent activation of the peroxisome proliferator-activated nuclear receptor-γ in macrophages. Experiments using specific cyclooxygenase (COX) inhibitors and genetic knockdown approaches indicated that COX-1, and not the COX-2 pathway, was responsible for the increased synthesis of 15d-PGJ2 in selenium-supplemented macrophages. Taken together, our results suggest that selenium supplementation increases the production of 15d-PGJ2 as an adaptive response to protect cells against oxidative stress-induced pro-inflammatory gene expression. More specifically, modification of protein thiols by 15d-PGJ2 represents a previously undescribed code for redox regulation of gene expression by selenium.

AB - Selenium is an essential micronutrient that suppresses the redox-sensitive transcription factor NF-κB-dependent pro-inflammatory gene expression. To understand the molecular mechanisms underlying the anti-inflammatory property of selenium, we examined the activity of a key kinase of the NF-κB cascade, IκB-kinase β (IKKβ) subunit, as a function of cellular selenium status in murine primary bone marrow-derived macrophages and RAW264.7 macrophage-like cell line. In vitro kinase assays revealed that selenium supplementation decreased the activity of IKKβ in lipopolysaccharide (LPS)-treated macrophages. Stimulation by LPS of selenium-supplemented macrophages resulted in a time-dependent increase in 15-deoxy-Δ 12,14-prostaglandin J2 (15d-PGJ2) formation, an endogenous inhibitor of IKKβ activity. Further analysis revealed that inhibition of IKKβ activity in selenium-supplemented cells correlated with the Michael addition product of 15d-PGJ2 with Cys-179 of IKKβ, while the formation of such an adduct was significantly decreased in the selenium-deficient macrophages. In addition, anti-inflammatory activities of selenium were also mediated by the 15d-PGJ2-dependent activation of the peroxisome proliferator-activated nuclear receptor-γ in macrophages. Experiments using specific cyclooxygenase (COX) inhibitors and genetic knockdown approaches indicated that COX-1, and not the COX-2 pathway, was responsible for the increased synthesis of 15d-PGJ2 in selenium-supplemented macrophages. Taken together, our results suggest that selenium supplementation increases the production of 15d-PGJ2 as an adaptive response to protect cells against oxidative stress-induced pro-inflammatory gene expression. More specifically, modification of protein thiols by 15d-PGJ2 represents a previously undescribed code for redox regulation of gene expression by selenium.

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