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

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

doi:10.1172/jci24895

Cited by 143 publications

(150 citation statements)

References 92 publications

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“…Thus, the widest difference in estrogen levels occurs between the follicular (lowest) and peri-ovulatory (highest) phases. Accordingly, in female donors, blood was drawn twice during the menstrual cycle (once during the follicular phase [about d [6][7][8] and once during the periovulatory phase [about d [13][14][15][16][17]). Peripheral blood T cells were exposed to increasing concentrations of β-estradiol and CREMα mRNA, and protein expression levels were assessed.…”

Section: Estrogen Increases Cremα Expression In T Cells From Men and mentioning

confidence: 99%

“…Thus, a balance between the expressions of these two transcription factors determines the occupancy of the IL-2 promoter and thus transcription (15). Increased expression of the protein phosphatase 2A (PP2A) enzyme in SLE T cells leads to dephosphorylation of CREB (16) and thus a tilting of the balance in favor of the CREMα repressor. Increased binding of CREMα to the IL-2 promoter is enabled by calcium-calmodulin kinase IV in SLE T cells (17).…”

Section: Introductionmentioning

confidence: 99%

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Estrogen Upregulates Cyclic AMP Response Element Modulator α Expression and Downregulates Interleukin-2 Production by Human T Lymphocytes

Moulton

Holcomb

Zajdel

et al. 2012

Mol Med

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Section: Estrogen Increases Cremα Expression In T Cells From Men and mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Estrogen Upregulates Cyclic AMP Response Element Modulator α Expression and Downregulates Interleukin-2 Production by Human T Lymphocytes

Moulton

Holcomb

Zajdel

et al. 2012

Mol Med

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“…PP2A has a tripartite structure consisting of the scaffold subunit A and the catalytic subunit C forming the core enzyme and one of the many regulatory subunits binding to the core enzyme to form a functional holoenzyme (8). We have shown previously that PP2A protein and mRNA levels as well as the enzymatic activity of the catalytic subunit are increased in T cells from SLE patients compared with healthy individuals (9). This enhanced expression of PP2A is one of the factors contributing to the molecular defects seen in SLE (10).…”

mentioning

confidence: 99%

Transcription factor Ikaros Represses Protein Phosphatase 2A (PP2A) Expression through an Intronic Binding Site

Nagpal

Watanabe

Tsao

et al. 2014

Journal of Biological Chemistry

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Background: PP2A is a serine/threonine phosphatase playing a central role in the pathology of the autoimmune disease SLE. Results: Ikaros binds to an intronic site in PP2A and modulates its expression. Conclusion: Ikaros represses PP2A expression by recruiting histone deacetylase HDAC1. Significance: This study proposes a novel pathway for regulation of PP2A, a critical molecule in SLE pathogenesis.

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“…It is the principal enzyme responsible for the dephosphorylation of CREB in T lymphocytes. PP2A levels, measured as protein and mRNA, are abnormally elevated in T cells from SLE patients [22]. PP2A activity is also augmented in lupus T cells and contributes to the defect in IL-2 production by altering the pCREB/CREM ratio.…”

Section: Pcreb and Cremmentioning

confidence: 99%

“…PP2A activity is also augmented in lupus T cells and contributes to the defect in IL-2 production by altering the pCREB/CREM ratio. The inhibition of PP2A in lupus T cells (by siRNA or by the expression of dominant negative isoforms) increases pCREB binding to the promoters of c-fos and IL-2 and, by doing so, corrects the IL-2 production defect [22]. Thus, T cells from patients with SLE have a number of alterations that add to blunt -by different mechanisms-their IL-2 producing capacity.…”

Section: Pcreb and Cremmentioning

confidence: 99%

Novel molecular targets in the treatment of systemic lupus erythematosus

Crispín

Tsokos

2008

Autoimmunity Reviews

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T cells from patients with systemic lupus erythematosus (SLE) display a number of biochemical abnormalities which include altered expression of key signaling molecules, heightened calcium responses, and skewed expression of transcription factors. These defects are involved in the altered behavior of SLE T cells and are probably central in the disease pathogenesis. The aim of this communication is to review the defects that have been consistently documented in SLE T cells, highlighting molecules and pathways that represent therapeutic targets. Keywordsautoimmunity; CD3ζ; pathogenesis; PP2A; systemic lupus erythematosus; therapyIn patients with autoimmune diseases, the immune system mounts full-scale responses against self constituents; it destroys self tissues using the same mechanisms it relies on when dealing with foreign noxious agents. Accordingly, the therapeutic actions of the drugs designed for the treatment of these conditions -whether conventional or biological-depend on their capacity to inhibit immune effector mechanisms. Thus, different degrees of immune suppression are implicit in their therapeutic capacity. The suppression of the immune system permits patients with autoimmune diseases to live better, longer lives, but is not able to cure them. Although in these conditions immune suppression is evidently useful, its use is always associated with the risk of infectious and malignant diseases.Patients with systemic lupus erythematosus (SLE) develop an immune response against a variety of ubiquitous antigens. Clinically, it manifests as a waxing and waning inflammatory disease whose intensity and organ involvement varies significantly. High concordance rates in monozygotic twins indicate that genetic factors play a major role in SLE development. In fact, polymorphisms of a number of genes have been linked to SLE. The mechanisms by which such polymorphisms contribute to disease expression are mostly unknown, however, the general assumption is that their presence causes functional changes in the immune response that make the system prone to autoreactivity when exposed to certain environmental or hormonal triggers. The risk imposed by the presence of each of the genetic factors associated

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

Cited by 143 publications

References 92 publications

Estrogen Upregulates Cyclic AMP Response Element Modulator α Expression and Downregulates Interleukin-2 Production by Human T Lymphocytes

Estrogen Upregulates Cyclic AMP Response Element Modulator α Expression and Downregulates Interleukin-2 Production by Human T Lymphocytes

Transcription factor Ikaros Represses Protein Phosphatase 2A (PP2A) Expression through an Intronic Binding Site

Novel molecular targets in the treatment of systemic lupus erythematosus

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