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Title

Inhibition of IkB kinase and IkB phosphorylation by 15-deoxy-Δ12,14 -prostaglandin J2 in activated murine macrophages

AuthorsCastrillo, Antonio CSIC; Díaz-Guerra, María José; Hortelano, Sonsoles; Martín-Sanz, Paloma ; Boscá, Lisardo CSIC ORCID CVN
Issue DateMar-2000
PublisherAmerican Society for Microbiology
CitationMolecular and Cellular Biology 20(5): 1692-1698 (2000)
AbstractActivation of the macrophage cell line RAW 264.7 with lipopolysaccharide (LPS) and gamma interferon (IFN-gamma) induces the expression of gene products involved in host defense, among them type 2 nitric oxide synthase. Treatment of cells with 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)) inhibited the LPS- and IFN-gamma-dependent synthesis of NO, a process that was not antagonized by similar concentrations of prostaglandin J(2), prostaglandin E(2), or rosiglitazone, a peroxisomal proliferator-activated receptor gamma ligand. Incubation of activated macrophages with 15dPGJ(2) inhibited the degradation of IkappaBalpha and IkappaBbeta and increased their levels in the nuclei. NF-kappaB activity, as well as the transcription of NF-kappaB-dependent genes, such as those encoding type 2 nitric oxide synthase and cyclooxygenase 2, was impaired under these conditions. Analysis of the steps leading to IkappaB phosphorylation showed an inhibition of IkappaB kinase by 15dPGJ(2) in cells treated with LPS and IFN-gamma, resulting in an impaired phosphorylation of IkappaBalpha, at least in the serine 32 residue required for targeting and degradation of this protein. Incubation of partially purified activated IkappaB kinase with 2 microM 15dPGJ(2) reduced by 83% the phosphorylation in serine 32 of IkappaBalpha, suggesting that this prostaglandin exerts direct inhibitory effects on the activity of the IkappaB kinase complex. These results show rapid actions of 15dPGJ(2), independent of peroxisomal proliferator receptor gamma activation, in macrophages challenged with low doses of LPS and IFN-gamma.
Description7 pages, 7 figures.
Publisher version (URL)http://dx.doi.org/10.1128/MCB.20.5.1692-1698.2000
URIhttp://hdl.handle.net/10261/24273
DOI10.1128/MCB.20.5.1692-1698.2000
ISSN0270-7306
Appears in Collections:(IIBM) Artículos

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