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Protein phosphatase 2A is a negative regulator of IL-2 production in patients with systemic lupus erythematosus
Christina G. Katsiari, … , Yuang-Taung Juang, George C. Tsokos
Christina G. Katsiari, … , Yuang-Taung Juang, George C. Tsokos
Published November 1, 2005
Citation Information: J Clin Invest. 2005;115(11):3193-3204. https://doi.org/10.1172/JCI24895.
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Research Article Immunology Article has an altmetric score of 3

Protein phosphatase 2A is a negative regulator of IL-2 production in patients with systemic lupus erythematosus

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Abstract

Decreased IL-2 production in systemic lupus erythematosus (SLE) represents a central component of the disease immunopathology. We report that the message, protein, and enzymatic activity of the catalytic subunit of protein phosphatase 2A (PP2Ac), but not PP1, are increased in patients with SLE regardless of disease activity and treatment and in a disease-specific manner. Treatment of SLE T cells with PP2Ac-siRNA decreased the protein levels and activity of PP2Ac in a specific manner and increased the levels of phosphorylated cAMP response element–binding protein and its binding to the IL2 and c-fos promoters, as well as increased activator protein 1 activity, causing normalization of IL-2 production. Our data document increased activity of PP2A as a novel SLE disease-specific abnormality and define a distinct mechanism whereby it represses IL-2 production. We propose the use of PP2Ac-siRNA as a novel tool to correct T cell IL-2 production in SLE patients.

Authors

Christina G. Katsiari, Vasileios C. Kyttaris, Yuang-Taung Juang, George C. Tsokos

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Figure 4

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PP2Ac enzymatic activity is increased in SLE T cells. PP2Ac enzymatic ac...
PP2Ac enzymatic activity is increased in SLE T cells. PP2Ac enzymatic activity was studied in peripheral blood T cells from patients with SLE or RA and normal subjects as described in Methods and is presented as picomoles PO43–/microgram of protein. PP2Ac protein levels were studied in parallel using Western blots. (A) Cumulative data of PP2Ac catalytic activity are presented. Statistical significance is also shown. (B) Results from a representative experiment are shown where PP2Ac enzymatic activity (upper panel: malachite green assay; phosphatase activity values [pmol PO43–/μg protein, mean ± SEM of triplicates] corresponding to each sample are noted below the panel) was assessed in parallel with PP2Ac protein levels (lower panel; PP2Ac/β-actin ratios are noted below the panel). Anti-IgG immunoprecipitates and β-actin protein levels were used as controls for the determination of the activity and the expression of PP2Ac, respectively. (C) Experiments performed to assess nonspecific results due to contamination with residual PO43– or with nonspecific immunoprecipitates. Enzymatic activity of anti-PP2Ac immunocomplexes was abolished in the presence of the Ser/Thr phosphatase inhibitor NaF (upper panel, representative of 6 experiments). Western blot analysis of the anti-PP2Ac immunoprecipitates detected only PP2Ac protein, whereas when the control anti-IgG Ab was used, no protein was precipitated (lower panel). (D) PP2Ac activity is increased in SLE T cells from patients with active and inactive disease, regardless of prednisone treatment. Results for patients receiving no, low dose (≤7.5 mg/d), or moderate dose (>7.5 to <40 mg/d) of prednisone as well as active (SLEDAI, 4–14) and inactive (SLEDAI, 0–3) patients are depicted separately.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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