MG132 proteasome inhibitor modulates proinflammatory cytokines production and expression of their receptors in U937 cells: involvement of nuclear factor-kappaB and activator protein-1.
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.
Ortiz-Lazareno
Pablo C
PC
División de Inmunología, Centro de Investigación Biomédica de Occidente del IMSS, Guadalajara, Jal. Mexico. paulcesar05@hotmail.com
Hernandez-Flores
Georgina
G
Dominguez-Rodriguez
Jorge R
JR
Lerma-Diaz
Jose M
JM
Jave-Suarez
Luis F
LF
Aguilar-Lemarroy
Adriana
A
Gomez-Contreras
Piedad C
PC
Scott-Algara
Daniel
D
Bravo-Cuellar
Alejandro
A
D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007976:Leupeptins / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D020298:U937 Cells
D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D020672:I-kappa B Proteins; C508590:IL1R1 protein, human; C508603:IL6R protein, human; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D007976:Leupeptins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018121:Receptors, Cytokine; D053573:Receptors, Interleukin-1 Type I; D019947:Receptors, Interleukin-6; D047888:Receptors, Tumor Necrosis Factor, Type I; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D013755:Tetradecanoylphorbol Acetate; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde