Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages
| Autor: | Aryan M. Namboodiri, Inderjit Singh, Faruk G. Sheikh, Kalipada Pahan |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Lipopolysaccharides
medicine.medical_treatment Farnesyl pyrophosphate Mevalonic Acid Mevalonic acid Pharmacology Nitric Acid chemistry.chemical_compound Polyisoprenyl Phosphates medicine Animals Humans Lovastatin Enzyme Inhibitors Cells Cultured Phenylacetates Alkyl and Aryl Transferases biology Microglia Interleukin-6 Tumor Necrosis Factor-alpha Anticholesteremic Agents Macrophages NF-kappa B General Medicine Rats Nitric oxide synthase Cytokine medicine.anatomical_structure Phenylacetate chemistry Biochemistry Astrocytes Enzyme Induction biology.protein Cytokines lipids (amino acids peptides and proteins) Mevalonate pathway Mitogens Nitric Oxide Synthase Sesquiterpenes Research Article Interleukin-1 medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 100:2671-2679 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci119812 |
| Popis: | This study explores the role of mevalonate inhibitors in the activation of NF-kbeta and the induction of inducible nitric oxide synthase (iNOS) and cytokines (TNF-alpha, IL-1beta, and IL-6) in rat primary astrocytes, microglia, and macrophages. Lovastatin and sodium phenylacetate (NaPA) were found to inhibit LPS- and cytokine-mediated production of NO and expression of iNOS in rat primary astrocytes; this inhibition was not due to depletion of end products of mevalonate pathway (e.g., cholesterol and ubiquinone). Reversal of the inhibitory effect of lovastatin on LPS-induced iNOS expression by mevalonate and farnesyl pyrophosphate and reversal of the inhibitory effect of NaPA on LPS-induced iNOS expression by farnesyl pyrophosphate, however, suggests a role of farnesylation in the LPS-mediated induction of iNOS. The inhibition of LPS-mediated induction of iNOS by FPT inhibitor II, an inhibitor of Ras farnesyl protein transferase, suggests that farnesylation of p21(ras) or other proteins regulates the induction of iNOS. Inhibition of LPS-mediated activation of NF-kbeta by lovastatin, NaPA, and FPT inhibitor II in astrocytes indicates that the observed inhibition of iNOS expression is mediated via inhibition of NF-kbeta activation. In addition to iNOS, lovastatin and NaPA also inhibited LPS-induced expression of TNF-alpha, IL-1beta, and IL-6 in rat primary astrocytes, microglia, and macrophages. This study delineates a novel role of the mevalonate pathway in controlling the expression of iNOS and different cytokines in rat astrocytes, microglia, and macrophages that may be important in developing therapeutics against cytokine- and NO-mediated neurodegenerative diseases. |
| Databáze: | OpenAIRE |
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