Deficient type I protein kinase A isozyme activity in systemic lupus erythematosus T lymphocytes.

Khan, Islam Ullah; Malemud, Charles J.

doi:10.1172/jci117340

Cited by 86 publications

(71 citation statements)

References 36 publications

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“…Several reports in the literature indicate that this may be the case. Patients with MS, rheumatoid arthritis, or lupus were found to have low intracellular cAMP levels (25,26), decreased expression and activity of G protein-coupled receptor kinases (27), or deficient type I cAMP-dependent protein kinase A activity (28,29). Similar abnormalities in cAMP signaling were suggested in asthmatic patients (30 -32).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of Phosphodiesterase-4 and -3 Inhibitors in Th1-Mediated Autoimmune Diseases

Bielekova

Lincoln

McFarland

et al. 2000

The Journal of Immunology

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Phosphodiesterase-4 (PDE4) inhibitors have the potential to modulate immune responses from the Th1 toward the Th2 phenotype and are considered candidate therapies for Th1-mediated autoimmune disorders. However, depending on the model and cell types employed, studies of atopic individuals have come to the opposite conclusion, i.e., that PDE inhibitors may be beneficial in asthma. Using in vitro immunopharmacologic techniques we analyzed the effects of PDE4 and PDE3 inhibitors on human immune cells to address these discrepancies and broaden our understanding of their mechanism of action. Our results indicate that PDE inhibitors have complex inhibitory effects within in vivo achievable concentration ranges on Th1-mediated immunity, whereas Th2-mediated responses are mostly unaffected or enhanced. The Th2 skewing of the developing immune response is explained by the effects of PDE inhibitors on several factors contributing to T cell priming: the cytokine milieu; the type of costimulatory signal, i.e., up-regulation of CD86 and down-regulation of CD80; and the Ag avidity. The combination of PDE4 and PDE3 inhibitors expresses synergistic effects and may broaden the therapeutic window. Finally, we observed a differential sensitivity to PDE inhibition in autoreactive vs foreign Ag-specific T cells and cells derived from multiple sclerosis patients vs those derived from healthy donors. This suggests that PDE inhibition weakens the strength of the T cell stimulus and corrects the underlying disease-associated cytokine skew in T cell-mediated autoimmune disorders. These new findings broaden the understanding of the immunomodulatory actions of PDE inhibitors and underscore their promising drug profile for the treatment of autoimmune disorders.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of Phosphodiesterase-4 and -3 Inhibitors in Th1-Mediated Autoimmune Diseases

Bielekova

Lincoln

McFarland

et al. 2000

The Journal of Immunology

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“…In a proportion of subjects with SLE, a deficiency of T cell protein kinase A (PKA) activity has been identified (1). This deficiency is a component of an overall signaling disorder that may contribute to altered T cell helper and cytotoxic functions (2).…”

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

Protein Kinase A Regulatory Subunit Type IIβ Directly Interacts with and Suppresses CREB Transcriptional Activity in Activated T Cells

Elliott

Tolnay

Tsokos

2003

The Journal of Immunology

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Levels of the type IIβ regulatory subunit (RIIβ) of protein kinase A are abnormally high in the nuclei of T cells of some subjects with the autoimmune disorder systemic lupus erythematosus (SLE). However, the role of nuclear RIIβ in the regulation of T cell function is unknown. Based on previous studies demonstrating that nuclear protein kinase A-RII subunits can modify cAMP response element (CRE)-dependent transcription, we tested the hypothesis that nuclear RIIβ can alter CRE-directed gene expression in T cells through interaction with the nuclear transcription factor CRE-binding protein CREB. To test this hypothesis, we used the RIIβ-deficient S49 and the Jurkat T cell lines. In both cell lines, transient transfection of RIIβ resulted in nuclear localization of a portion of the ectopically expressed RIIβ. In vitro and in vivo analyses revealed a novel, specific interaction between RIIβ and CREB that mapped to the N-terminal 135 aa of RIIβ. In functional studies, RIIβ inhibited the transcriptional activity of a GAL4-CREB fusion protein by 67% in Jurkat T cells following activation with anti-CD3 and anti-CD28 mAbs. Importantly, deletion of the CREB-binding region of RIIβ completely abrogated inhibition. Additionally, RIIβ suppressed CRE-directed reporter gene expression and substantially reduced induction of promoter activity and endogenous protein levels of the CREB-dependent gene, c-fos, in activated T cells. We conclude that nuclear RIIβ can act as a repressor of CREB transcriptional activity in T cells, providing a potential functional significance for aberrant levels of nuclear RIIβ in systemic lupus erythematosus T cells.

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“…Additionally, a wide variety of T cell signaling defects have been described in lupus T cells (for review, see refs. 12 and 13), including defects of T cell signaling through the T cell receptor (TCR) and through the protein kinase A pathway (14,15). Typically, in vitro restimulation is required to demonstrate defective T cell function in lupus T cells.…”

mentioning

confidence: 99%

Pathogenic T cells in murine lupus exhibit spontaneous signaling activity through phosphatidylinositol 3‐kinase and mitogen‐activated protein kinase pathways

Niculescu¹,

Nguyen²,

Niculescu³

et al. 2003

Arthritis & Rheumatism

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Objective. To determine the activation status of two cytoplasmic signaling pathways, phosphatidylinositol 3-kinase (PI 3-kinase) and the mitogen-activated protein kinase (MAPK) family.Methods. We studied the pathogenic CD4؉ T cells that drive disease in the parent-into-F 1 mouse model of lupus-like chronic graft-versus-host disease (GVHD). We determined immunoprecipitated kinase activity for PI 3-kinase and MAPK members ( Results. Compared with negative controls, unfractionated splenocyte kinase activity from chronic GVHD mice was significantly increased for PI 3-kinase and JNK-1, but not for Raf-1, p38 MAPK, or ERK-1. Increased PI 3-kinase and JNK-1 activity was also seen in acute GVHD splenocytes, as was increased Raf-1 and p38 MAPK activity. The pattern of increased PI 3-kinase and JNK-1 activity seen in unfractionated chronic GVHD splenocytes was also seen in isolated donor, but not host, CD4؉ T cells from chronic GVHD mice, indicating that donor CD4؉ T cell signaling activity accounted for at least a portion of the activity observed in unfractionated splenocytes. Increased ERK-1 activity was not seen in either donor or host CD4؉ T cells. This pattern of cytoplasmic signaling pathway in donor CD4؉ T cells was associated with increased T cell receptor membrane signaling activation (Lck and Fyn phosphorylation) and increased transcription activation (phosphorylation of inhibitor of nuclear factor B), confirming the biologic significance of these observations. Conclusion. The pathogenic T cells driving disease in this murine model exhibit activation in the form of spontaneous cytoplasmic signaling pathway activity that can be detected without in vitro restimulation and involves a T cell-specific (PI 3-kinase) and a nonspecific stress/cytokine pathway (JNK-1). These results raise the possibility that a full characterization of the signaling pathways active in pathogenic lupus T cells might lead to new therapeutic targets.

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Deficient type I protein kinase A isozyme activity in systemic lupus erythematosus T lymphocytes.

Cited by 86 publications

References 36 publications

Therapeutic Potential of Phosphodiesterase-4 and -3 Inhibitors in Th1-Mediated Autoimmune Diseases

Therapeutic Potential of Phosphodiesterase-4 and -3 Inhibitors in Th1-Mediated Autoimmune Diseases

Protein Kinase A Regulatory Subunit Type IIβ Directly Interacts with and Suppresses CREB Transcriptional Activity in Activated T Cells

Pathogenic T cells in murine lupus exhibit spontaneous signaling activity through phosphatidylinositol 3‐kinase and mitogen‐activated protein kinase pathways

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