The anti-inflammatory effects of selenium are mediated through 15-deoxy-Delta12,14-prostaglandin J2 in macrophages.
Selenium is an essential micronutrient that suppresses the redox-sensitive transcription factor NF-kappaB-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-kappaB cascade, IkappaB-kinase beta (IKKbeta) 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 IKKbeta in lipopolysaccharide (LPS)-treated macrophages. Stimulation by LPS of selenium-supplemented macrophages resulted in a time-dependent increase in 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) formation, an endogenous inhibitor of IKKbeta activity. Further analysis revealed that inhibition of IKKbeta activity in selenium-supplemented cells correlated with the Michael addition product of 15d-PGJ2 with Cys-179 of IKKbeta, 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-gamma 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.
Vunta
Hema
H
Department of Veterinary and Biomedical Sciences, Centers for Molecular Toxicology and Carcinogenesis, and Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania 16802.
Davis
Faith
F
Department of Veterinary and Biomedical Sciences, Centers for Molecular Toxicology and Carcinogenesis, and Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania 16802.
Palempalli
Umamaheswari D
UD
Department of Veterinary and Biomedical Sciences, Centers for Molecular Toxicology and Carcinogenesis, and Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania 16802.
Bhat
Deepa
D
Department of Veterinary and Biomedical Sciences, Centers for Molecular Toxicology and Carcinogenesis, and Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania 16802.
Arner
Ryan J
RJ
Department of Veterinary and Biomedical Sciences, Centers for Molecular Toxicology and Carcinogenesis, and Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania 16802.
Thompson
Jerry T
JT
Department of Veterinary and Biomedical Sciences, Centers for Molecular Toxicology and Carcinogenesis, and Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania 16802.
Peterson
Devin G
DG
Department of Food Science, Pennsylvania State University, University Park, Pennsylvania 16802.
Reddy
C Channa
CC
Department of Veterinary and Biomedical Sciences, Centers for Molecular Toxicology and Carcinogenesis, and Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania 16802. Electronic address: ccr1@psu.edu.
Prabhu
K Sandeep
KS
Department of Veterinary and Biomedical Sciences, Centers for Molecular Toxicology and Carcinogenesis, and Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania 16802. Electronic address: ksp4@psu.edu.
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000737:chemistry; D002460:Cell Line; D003545:Cysteine / Q000737:chemistry; D005786:Gene Expression Regulation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism; D012643:Selenium / Q000737:chemistry / Q000494:pharmacology*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047495:PPAR gamma; D016718:Arachidonic Acid; D012643:Selenium; D003545:Cysteine; D015230:Prostaglandin D2