Inhibition of nuclear factor kappa B by prostaglandin A1: an effect associated with heat shock transcription factor activation.
Prostaglandins (PGs) function as intracellular signal mediators in the regulation of a variety of physiological and pathological processes, including inflammation and immune responses. Cyclopentenone PGs are characterized by antiviral activity against several viruses, including human immunodeficiency virus type 1 (HIV-1), and by the ability to induce heat shock protein expression through activation of the heat shock transcription factor. Here we report that PGA1 is a potent inhibitor of nuclear factor-kappa B (NF-kappa B) activation in human cells and of NF-kappa B-dependent HIV-1 transcription in long terminal repeat-chloramphenicol acetyl-transferase transient transfection experiments. PGA1 acts by inhibiting phosphorylation and preventing degradation of the NF-kappa B inhibitor I kappa B-alpha. Inhibition does not require protein synthesis, is dependent on the presence of a reactive cyclopentenonic moiety, and is associated with heat shock transcription factor activation. Because NF-kappa B is critically involved in the activation of immunoregulatory and viral genes, inhibition of its activity could be a major component of the immunosuppressive and antiviral activity of PGs.
Rossi
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A
Institute of Experimental Medicine, Consiglio Nazionale delle Ricerche, Rome, Italy.
Elia
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Santoro
M G
MG
D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000502:physiology*; D015777:Eicosanoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000235:genetics; D000076249:Heat Shock Transcription Factors; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D011454:Prostaglandins A / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D015777:Eicosanoids; D000076249:Heat Shock Transcription Factors; D016328:NF-kappa B; D011454:Prostaglandins A; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; D014157:Transcription Factors; D051841:Transcription Factor RelB; D003513:Cycloheximide; C100573:prostaglandin A1