Aurothiomalate inhibits the expression of mPGES-1 in primary human chondrocytes

Tuure, Lauri; Hämäläinen, Mari; Moilanen, Teemu; Moilanen, Eeva

doi:10.3109/03009742.2014.927917

Cited by 5 publications

(3 citation statements)

References 24 publications

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“…Using a cryostat, 40 μm serial sections in the horizontal plane were collected throughout the brain. Free-floating sections were blocked with 10% normal goat serum (Jackson ImmunoResearch Laboratories) and 0.4% Triton X-100 in PBS for 1 h and incubated in PBS containing 0.1% Triton X-100 and primary antibodies against PgE 2 synthase (anti-mPgES-1) (Olajide et al, 2014; Tuure et al, 2015) (Agrisera, catalog #AS03 031, 1:200) as well as an astrocyte phenotypic marker (anti-GFAP (Lathia et al, 2008) (Sigma, catalog #G3893, clone #G-A-5, 1:500) overnight at 4°C. Tissue was rinsed and incubated in AlexaFluor-488 goat anti-mouse and AlexaFluor-546 goat anti-rabbit secondary antibodies (Invitrogen: diluted 1:500 in PBS, 2.5% normal goat serum and 0.4% Triton X-100) for 1.5 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

A Critical Role for Astrocytes in Hypercapnic Vasodilation in Brain

et al. 2017

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Cerebral blood flow (CBF) is controlled by arterial blood pressure, arterial CO2, arterial O2, and brain activity and is largely constant in the awake state. Although small changes in arterial CO2 are particularly potent to change CBF (1 mmHg variation in arterial CO2 changes CBF by 3%–4%), the coupling mechanism is incompletely understood. We tested the hypothesis that astrocytic prostaglandin E2 (PgE2) plays a key role for cerebrovascular CO2 reactivity, and that preserved synthesis of glutathione is essential for the full development of this response. We combined two-photon imaging microscopy in brain slices with in vivo work in rats and C57BL/6J mice to examine the hemodynamic responses to CO2 and somatosensory stimulation before and after inhibition of astrocytic glutathione and PgE2 synthesis. We demonstrate that hypercapnia (increased CO2) evokes an increase in astrocyte [Ca2+]i and stimulates COX-1 activity. The enzyme downstream of COX-1 that synthesizes PgE2 (microsomal prostaglandin E synthase-1) depends critically for its vasodilator activity on the level of glutathione in the brain. We show that, when glutathione levels are reduced, astrocyte calcium-evoked release of PgE2 is decreased and vasodilation triggered by increased astrocyte [Ca2+]i in vitro and by hypercapnia in vivo is inhibited. Astrocyte synthetic pathways, dependent on glutathione, are involved in cerebrovascular reactivity to CO2. Reductions in glutathione levels in aging, stroke, or schizophrenia could lead to dysfunctional regulation of CBF and subsequent neuronal damage.SIGNIFICANCE STATEMENT Neuronal activity leads to the generation of CO2, which has previously been shown to evoke cerebral blood flow (CBF) increases via the release of the vasodilator PgE2. We demonstrate that hypercapnia (increased CO2) evokes increases in astrocyte calcium signaling, which in turn stimulates COX-1 activity and generates downstream PgE2 production. We demonstrate that astrocyte calcium-evoked production of the vasodilator PgE2 is critically dependent on brain levels of the antioxidant glutathione. These data suggest a novel role for astrocytes in the regulation of CO2-evoked CBF responses. Furthermore, these results suggest that depleted glutathione levels, which occur in aging and stroke, will give rise to dysfunctional CBF regulation and may result in subsequent neuronal damage.

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Section: Methodsmentioning

confidence: 99%

A Critical Role for Astrocytes in Hypercapnic Vasodilation in Brain

et al. 2017

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“…Microsomal prostaglandin E synthase-1 is an inducible inflammatory enzyme, the expression of which has been reported to be inhibited by glucocorticoids (Stichtenoth et al, 2001 ; Tuure et al, 2015 ). The present study extends the previous data by showing that the glucocorticoid effect on mPGES-1 is mediated through enhanced expression of the regulatory phosphatase MKP-1 and subsequent dephosphorylation of the MAP kinase JNK in inflammatory conditions.…”

Section: Discussionmentioning

confidence: 99%

Microsomal Prostaglandin E Synthase-1 Expression in Inflammatory Conditions Is Downregulated by Dexamethasone: Seminal Role of the Regulatory Phosphatase MKP-1

2017

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Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme situated downstream of cyclo-oxygenase-2, promoting the excessive PGE2 production in inflammation. Dexamethasone is known to suppress mPGES-1 but the mechanisms regulating mPGES-1 expression remain poorly known. MKP-1 is a phosphatase controlling the proinflammatory MAP kinase pathways p38 and JNK, thus limiting the inflammatory responses. We have now investigated the role of MKP-1 and MAP kinases p38 and JNK in the regulation of mPGES-1 expression by dexamethasone. Dexamethasone increased MKP-1 and decreased mPGES-1 expression in J774 macrophages and in peritoneal macrophages from wild-type but not from MKP-1 deficient mice. Dexamethasone also reduced p38 and JNK phosphorylation along with enhancement of MKP-1, while inhibition of JNK reduced mPGES-1 expression. These findings were also translated to in vivo conditions as dexamethasone downregulated mPGES-1 expression in paw inflammation in wild-type but not in MKP-1 deficient mice. In conclusion, dexamethasone was found to downregulate mPGES-1 expression through enhanced MKP-1 expression and reduced JNK phosphorylation in inflammatory conditions. The results extend the understanding on the regulation of mPGES-1 expression and highlight the potential of MKP-1 as an anti-inflammatory drug target.

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“…; Tuure et al. ). In addition, mPGES‐1 expression has been reported to be upregulated by p38 and/or JNK MAP kinases.…”

Section: Introductionmentioning

confidence: 97%

PDE4 inhibitor rolipram inhibits the expression of microsomal prostaglandin E synthase‐1 by a mechanism dependent on MAP kinase phosphatase‐1

Tuure

Hämäläinen

Moilanen

2017

Pharmacology Res & Perspec

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Phosphodiesterase‐4 (PDE4) inhibitors have recently been introduced to the treatment of COPD and psoriatic arthritis. Microsomal prostaglandin E synthase‐1 (mPGES‐1) is an inducible enzyme synthesizing PGE 2, the most abundant prostanoid related to inflammation and inflammatory pain. mPGES‐1 is a potential drug target for novel anti‐inflammatory treatments aiming at an improved safety profile as compared to NSAIDs. Here we investigated the effect of the PDE4 inhibitor rolipram on the expression of mPGES‐1 in macrophages; and a potential mediator role in the process for MAP kinase phosphatase‐1 (MKP‐1) which is an endogenous factor limiting the activity of the proinflammatory MAP kinases p38 and JNK. The expression of mPGES‐1 was decreased, whereas that of MKP‐1 was enhanced by rolipram in wild‐type murine macrophages. Interestingly, rolipram did not reduce mPGES‐1 expression in peritoneal macrophages from MKP‐1‐deficient mice. A reduced phosphorylation of JNK, but not p38 MAP kinase, was specifically associated with the decreased expression of mPGES‐1. Accordingly, mPGES‐1 expression was suppressed by JNK but not p38 inhibitor. These findings underline the significance of the increased MKP‐1 expression and decreased JNK phosphorylation associated with the downregulated expression of mPGES‐1 by PDE4 inhibitors in inflammation.

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Aurothiomalate inhibits the expression of mPGES-1 in primary human chondrocytes

Cited by 5 publications

References 24 publications

A Critical Role for Astrocytes in Hypercapnic Vasodilation in Brain

A Critical Role for Astrocytes in Hypercapnic Vasodilation in Brain

Microsomal Prostaglandin E Synthase-1 Expression in Inflammatory Conditions Is Downregulated by Dexamethasone: Seminal Role of the Regulatory Phosphatase MKP-1

PDE4 inhibitor rolipram inhibits the expression of microsomal prostaglandin E synthase‐1 by a mechanism dependent on MAP kinase phosphatase‐1

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