1. MG132 proteasome inhibitor modulates proinflammatory cytokines production and expression of their receptors in U937 cells: involvement of nuclear factor-kappaB and activator protein-1.
- Author
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Ortiz-Lazareno PC, Hernandez-Flores G, Dominguez-Rodriguez JR, Lerma-Diaz JM, Jave-Suarez LF, Aguilar-Lemarroy A, Gomez-Contreras PC, Scott-Algara D, and Bravo-Cuellar A
- Subjects
- Cells, Cultured, Cysteine Proteinase Inhibitors pharmacology, Humans, I-kappa B Proteins metabolism, Interleukin-1beta biosynthesis, Interleukin-6 biosynthesis, Lipopolysaccharides immunology, NF-kappa B metabolism, Receptors, Interleukin-1 Type I metabolism, Receptors, Interleukin-6 metabolism, Receptors, Tumor Necrosis Factor, Type I metabolism, Tetradecanoylphorbol Acetate immunology, Transcription Factor AP-1 metabolism, Tumor Necrosis Factor-alpha biosynthesis, U937 Cells, Cytokines biosynthesis, Inflammation Mediators metabolism, Leupeptins pharmacology, Receptors, Cytokine metabolism
- Abstract
In response to inflammatory stimuli, monocytes/macrophages secrete greater quantities of the proinflammatory cytokines tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and IL-6. The inflammatory process and the innate immune response are related to the activation of several transcription factors, such as nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1). The proteasome is a multimeric protease complex, which plays a vital role in several cellular functions, including the regulation of transcription factors like NF-kappaB. In this study, we used the human monocyte cell line U937 stimulated with lipopolysaccharide (LPS) and phorbol 12-myristate 13-acetate (PMA) as a model to investigate the in vitro effects of MG132, a proteasome inhibitor, on the release of TNF-alpha, IL-1beta and IL-6 and on the expression of their membrane and soluble receptors TNF-R1, IL-1R1 and IL-6R. We also analysed the effects of MG132 on the activation of NF-kappaB and AP-1 and on the IkappaB molecule. MG132 significantly inhibited the secretion of those proinflammatory cytokines. MG132 increased the release of the soluble receptors TNF-R1 and IL-1R1 from U937 cells and decreased their cell-surface expression. MG132 also increased IL-6R cell-surface expression and decreased its release. Proteasome inhibition also led to an increase in LPS+PMA-induced AP-1 activation and the attenuation of LPS+PMA-induced IkappaB degradation, resulting in the abolition of NF-kappaB activation. Our experiments strongly suggest that the proteasome is an important factor in the regulation of proinflammatory cytokines and their receptors.
- Published
- 2008
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