Cyclic AMP level of lymphocytes in patients with systemic lupus erythematosus and its relation to disease activity

Phi, Nguyen Chi; Takáts,; Binh, Vu Hoa; Vien, Cao Van; González-Cabello,; Palla, Gergely

doi:10.1016/0165-2478(89)90156-9

Cited by 10 publications

(4 citation statements)

References 19 publications

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“…Ongoing agonist-independent activation of AC would be expected to produce elevated levels of intracellular cAMP in SLE T lymphocytes. However, we and others have found that intracellular cAMP levels in SLE T cells are similar to those of normal controls (8,33 (35). Mutations of the a, gene can produce constitutive activation of AC.…”

Section: Discussionmentioning

confidence: 99%

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

Khan¹,

Malemud²

1994

J. Clin. Invest.

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Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by a dysfunctional cellular immune response. We have previously identified a metabolic disorder of the adenylate cyclase/cAMP/ protein kinase A (AC/cAMP/PKA) pathway characterized by impaired cAMP-inducible, PKA-catalyzed protein phosphorylation in intact T lymphocytes from subjects with severe SLE disease activity. Because this metabolic disorder may contribute to abnormal T cell immune effector functions, we tested the hypothesis that impaired PKA-dependent protein phosphorylation is the result of a PKA isozyme deficiency in SLE T lymphocytes. Compared with healthy and rheumatoid arthritis (RA) controls, subjects with severe SLE activity exhibited reduced PKA-catalyzed phosphorylation of proteins in the T lymphocyte plasma membrane where the type I isozyme of PKA (PKA-I) is predominantly localized. Both silver staining and biosynthetic labeling of membrane-associated proteins with [3S]-methionine demonstrated that reduced protein phosphorylation was not due to either an altered distribution of or absence of proteins. Moreover, phosphorylation of SLE membrane-associated proteins with the PKA catalytic (C) subunit showed a similar distribution and extent of phosphorylation compared with membrane proteins from healthy T cells, suggesting that SLE T cell membrane proteins could be phosphorylated. Sequential column chromatography of the type I and type II isozymes of PKA (PKA-I, PKA-ll) demonstrated a deficiency of PKA-I isozyme activity. Compared with a ratio of PKA-I to PKA-ll activity of 4.2:1 in healthy T cells, the activity ratio in T cells from subjects with severe SLE disease activity was O.99:1 (P = 0.01, SLE versus healthy controls for PKA-I). The deficient PKA-I activity was associated with a significant increase of free C-subunit activity (P = 0.04, SLE versus healthy controls for C-subunit). T cells from subjects with

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Section: Discussionmentioning

confidence: 99%

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

Khan¹,

Malemud²

1994

J. Clin. Invest.

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“…SLE patients have defects in the adenylate cyclase pathway in PBMCs, including T cells, and lupus-prone MRL/lpr mice also exert low cAMP levels in renal tissues [ 39 , 40 , 41 ]. In this study, ALD-DNA-stimulated macrophages show decreased cAMP levels, which may block glycogenolysis and lead to glycogen accumulation.…”

Section: Discussionmentioning

confidence: 99%

Activated Lymphocyte-Derived DNA Drives Glucose Metabolic Adaptation for Inducing Macrophage Inflammatory Response in Systemic Lupus Erythematosus

Zhao,

Wen,

Xiong

2023

Cells

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Activated lymphocyte-derived DNA (ALD-DNA) has been reported to drive the polarization of macrophages toward M2b, producing inflammatory cytokines and inducing inflammation, correspondingly playing an essential role in the development of systemic lupus erythematosus (SLE). Recently, accumulating evidence has pinpointed metabolic adaptation as the crucial cell-intrinsic determinant for inflammatory response, in which glucose metabolism is the key event. However, whether and how glucose metabolism was involved in ALD-DNA-induced macrophage inflammatory response and SLE development remains unclear. Herein, we performed glucose metabolomic analyses of ALD-DNA-stimulated macrophages and uncovered increased glycolysis and diminished pentose phosphate pathway (PPP), as well as enhanced glycogenesis. In ALD-DNA-stimulated macrophages, increased glycolysis resulted in higher lactate production, whereas diminished PPP efficiently led to lower levels of nicotinamide adenine dinucleotide phosphate (NADPH) with higher levels of reactive oxygen species (ROS). While blockade of lactate generation exerted no significant effect on macrophage inflammation in response to ALD-DNA, scavenging ROS fundamentally inhibited the inflammatory response of ALD-DNA-stimulated macrophages. Further, cyclic adenosine monophosphate (cAMP), a master for regulating glycogen metabolism, was downregulated by ALD-DNA in macrophages, which subsequently imbalanced glycogen metabolism toward glycogenesis but not glycogenolysis. Administration of cAMP effectively restored glycogenolysis and enhanced PPP, which correspondingly reduced ROS levels and inhibited the inflammatory response of ALD-DNA-stimulated macrophages. Finally, blocking glucose metabolism using 2-deoxy-D-glucose (2-DG) efficiently restricted macrophage inflammatory response and alleviated ALD-DNA-induced lupus disease. Together, our findings demonstrate that ALD-DNA drives the adaptation of glucose metabolism for inducing macrophage inflammatory response in SLE, which might further our understanding of disease pathogenesis and provide clues for interventive explorations.

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“…However, synthesis of activated TGF-␤ by NK cells is markedly depressed in SLE (51), making it unlikely that the AC/cAMP/PKA pathway is being spontaneously activated via binding of TGF-␤ to its cell surface receptors. Moreover, PKA is unlikely to be activated by enhanced cAMP binding to RII␤ subunits, for we know that basal intracellular cAMP concentrations are comparable in unstimulated SLE and control T cells (52,53). Additionally, if the PKA-II isozyme is like the PKA-I isozyme (15), the apparent K a for PKA-II may be increased and would require higher concentrations of endogenous cAMP to activate the isozyme.…”

Section: Discussionmentioning

confidence: 99%

Association of Deficient Type II Protein Kinase A Activity with Aberrant Nuclear Translocation of the RIIβ Subunit in Systemic Lupus Erythematosus T Lymphocytes

Mishra

Khan

Tsokos

2000

The Journal of Immunology

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Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by abnormal T cell signal transduction and altered T cell effector functions. We have previously observed a profound deficiency of total protein kinase A (PKA) phosphotransferase activity in SLE T cells. Here we examined whether reduced total PKA activity in SLE T cells is in part the result of deficient type II PKA (PKA-II) isozyme activity. The mean PKA-II activity in SLE T cells was 61% of normal control T cells. The prevalence of deficient PKA-II activity in 35 SLE subjects was 37%. Deficient isozyme activity was persistent over time and was unrelated to SLE disease activity. Reduced PKA-II activity was associated with spontaneous dissociation of the cytosolic RIIβ2C2 holoenzyme and translocation of the regulatory (RIIβ) subunit from the cytosol to the nucleus. Confocal immunofluorescence microscopy revealed that the RIIβ subunit was present in ∼60% of SLE T cell nuclei compared with only 2–3% of normal and disease controls. Quantification of nuclear RIIβ subunit protein content by immunoprecipitation and immunoblotting demonstrated a 54% increase over normal T cell nuclei. Moreover, the RIIβ subunit was retained in SLE T cell nuclei, failed to relocate to the cytosol, and was associated with a persistent deficiency of PKA-II activity. In conclusion, we describe a novel mechanism of deficient PKA-II isozyme activity due to aberrant nuclear translocation of the RIIβ subunit and its retention in the nucleus in SLE T cells. Deficient PKA-II activity may contribute to impaired signaling in SLE T cells.

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Cyclic AMP level of lymphocytes in patients with systemic lupus erythematosus and its relation to disease activity

Cited by 10 publications

References 19 publications

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

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

Activated Lymphocyte-Derived DNA Drives Glucose Metabolic Adaptation for Inducing Macrophage Inflammatory Response in Systemic Lupus Erythematosus

Association of Deficient Type II Protein Kinase A Activity with Aberrant Nuclear Translocation of the RIIβ Subunit in Systemic Lupus Erythematosus T Lymphocytes

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