The anti-inflammatory potency of dexamethasone is determined by the route of application in vivo

Weichhart, Thomas; Brandt, Oliver; Lassnig, Caroline; Müller, Mathias; Hörl, Walter H.; Stingl, Georg; Säemann, Marcus D.

doi:10.1016/j.imlet.2009.12.025

Cited by 14 publications

(12 citation statements)

References 17 publications

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“…On the day of the LPS challenge, some groups were additionally treated with 300 g/kg dexamethasone subcutaneously or vehicle; and after 30 minutes, mice were challenged intraperitoneally with 20 mg/kg or 10 mg/kg LPS as indicated. 38 Survival was monitored twice daily for 156 hours. All animal experiments were discussed and approved by the institutional ethics committee and the Austrian laws (GZ 68.205/0204-C/GT/2007 and GZ 68.205/0053-II/10b/2008).…”

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confidence: 99%

Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells

Weichhart

Haidinger

Karl

et al. 2011

Blood

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107

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A central role for the mammalian target of rapamycin (mTOR) in innate immunity has been recently defined by its ability to limit proinflammatory mediators. Although glucocorticoids (GCs) exert potent anti-inflammatory effects in innate immune cells, it is currently unknown whether the mTOR pathway interferes with GC signaling. Here we show that inhibition of mTOR with rapamycin or Torin1 prevented the anti-inflammatory potency of GC both in human monocytes and myeloid dendritic cells. GCs could not suppress nuclear factor-B and JNK activation, the expression of proinflammatory cytokines, and the promotion of Th1 responses when mTOR was inhibited. Interestingly, long-term activation of monocytes with lipopolysaccharide enhanced the expression of TSC2, the principle negative regulator of mTOR, whereas dexamethasone blocked TSC2 expression and reestablished mTOR activation. IntroductionCurrent immunosuppressive regimens to avoid allogeneic rejection after organ or bone marrow transplantation largely rely on drugs with potent immunosuppressive effects predominantly affecting different steps during T-cell activation. There is, however, increasing evidence that also the innate immune system is critical for the fate of allografts and may as well exert detrimental effector functions. 1-9 For example, monocytes are the first cells to enter the allograft immediately after transplantation; and recently, monocyte influx, rather than T-cell influx, into the allograft has been proposed to correlate with graft rejection. 9 Monocytes, macrophages, and dendritic cells (DCs) initiate the inflammatory response after stimulation by Toll-like receptor (TLR) ligands and trigger the subsequent adaptive T-cell response. 10,11 However, the molecular pathways targeted by immunosuppressants in particular when they are used as combination therapy and the ensuing functional consequences are still incompletely defined.Among the currently used immunosuppressants calcineurin inhibitors (CNI), such as cyclosporine A (CsA) or FK506, and antimetabolites, such as mycophenolic acid (mycophenolate mofetil [MMF]) are thought to exert distinct but rather modest effects on innate immune cells. 12,13 On the contrary, glucocorticoids (GCs) have a high anti-inflammatory potential and, consequently, are crucial constituents of various immunosuppressive regimens applied in many inflammatory conditions. 14 GCs differentially affect cytokine production in monocytes/macrophages with a prominent shift toward an anti-inflammatory phenotype. 15 Furthermore, DC differentiation and maturation are profoundly suppressed by GCs, leading to DCs with a tolerizing capacity characterized by increased interleukin-10 (IL-10), but blocked IL-12 secretion. 16,17 At the molecular level, GCs profoundly inhibit nuclear factor-B (NF-B) signaling via the glucocorticoid receptor (GR) to prevent recruitment of active NF-B dimers to the B promoter. 18 Moreover, it has been demonstrated that the c-Jun N-terminal kinase (JNK) pathway that specifically leads to the activation of the tr...

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confidence: 99%

Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells

Weichhart

Haidinger

Karl

et al. 2011

Blood

Self Cite

123

107

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“…Although the exact mechanism of action is unknown, DEX acts on a variety of immune cell types, including macrophages, neutrophils and epithelial cells, and suppresses the production of pro-inflammatory cytokines [32], [33]. Specifically, DEX protects mice against high dose-LPS mediated lethality by reducing TNFα and IL-6 expression through a variety of intracellular signalling pathways [33].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to this direct anti-endotoxin effect, LL-37 is able to modulate Toll-like receptor activation and pro-inflammatory gene transcription. Dexamethasone (DEX – Sigma-Aldrich Canada) is an anti-inflammatory glucocorticoid and has been shown previously to suppress the immune response to LPS [32], [33] and to provide some protection against Stx2 challenge [34]. For LL-37, HuSAP+ mice were IP injected with 225 pg/g BW Stx2 and 300 ng/g BW LPS either alone or admixed with 0.5 or 5.0 µg/g BW LL-37.…”

Section: Methodsmentioning

confidence: 99%

“…For LL-37, HuSAP+ mice were IP injected with 225 pg/g BW Stx2 and 300 ng/g BW LPS either alone or admixed with 0.5 or 5.0 µg/g BW LL-37. For DEX, HuSAP+ or WT mice were subcutaneously injected with 2.5 µg/g BW DEX or control saline 30 minutes prior to the IP injection of Stx2 and LPS, according to a previously published protocol for LPS neutralization [32]. Mice were weighed and monitored for signs of Shigatoxemia over a period of 150 h. In a separate experiment, HuSAP+ mice were euthanized by CO 2 asphyxiation and exsanguinated by cardiac puncture at 2 and 48 h for assessment of gene expression and serum cytokine concentrations as described in the previous section.…”

Section: Methodsmentioning

confidence: 99%

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Lipopolysaccharide Renders Transgenic Mice Expressing Human Serum Amyloid P Component Sensitive to Shiga Toxin 2

et al. 2011

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Transgenic C57BL/6 mice expressing human serum amyloid P component (HuSAP) are resistant to Shiga toxin 2 (Stx2) at dosages that are lethal in HuSAP-negative wild-type mice. However, it is well established that Stx2 initiates extra-intestinal complications such as the haemolytic-uremic syndrome despite the presence of HuSAP in human sera. We now demonstrate that co-administering purified Escherichia coli O55 lipopolysaccharide (LPS), at a dosage of 300 ng/g body weight, to HuSAP-transgenic mice increases their susceptibility to the lethal effects of Stx2. The enhanced susceptibility to Stx2 correlated with an increased expression of genes encoding the pro-inflammatory cytokine TNFα and chemokines of the CXC and CC families in the kidneys of LPS-treated mice, 48 hours after the Stx2/LPS challenge. Co-administering the glucocorticoid dexamethasone, but not the LPS neutralizing cationic peptide LL-37, protected LPS-sensitized HuSAP-transgenic mice from lethal doses of Stx2. Dexamethasone protection was specifically associated with decreased expression of the same inflammatory mediators (CXC and CC-type chemokines and TNFα) linked to enhanced susceptibility caused by LPS. The studies reveal further details about the complex cascade of host-related events that are initiated by Stx2 as well as establish a new animal model system in which to investigate strategies for diminishing serious Stx2-mediated complications in humans infected with enterohemorrhagic E. coli strains.

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“…For instance, the marketed form of Dex, surodex Õ (Sunnyvale, CA), has been widely used in surgery of glaucoma (Tan et al, 1999). But high-dose and long-term systemic administration of corticoids can cause serious side effects such as diabetes, glaucoma, hemorrhagic ulcers, skin atrophy, myopathies, osteoporosis and psychosis and have restricted for use in prolonged therapy (Koschinsky & Heinemann, 2001;Weichhart et al, 2010). Thus, to decrease these side effects, the new drug-controlled delivery systems for controlling inflammation response have been devised in this study.…”

Section: Introductionmentioning

confidence: 99%

PLA/PEG-PPG-PEG/Dexamethasone implant prepared by hot-melt extrusion for controlled release of immunosuppressive drug to implantable medical devices, part 2:in vivoevaluation

Li¹,

Guo²,

Deng³

et al. 2013

Drug Delivery

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Hot-melt extrusion (HME) plays an important role in preparing implants as local drug delivery systems in pharmaceutical fields. Here, a new PLA/PEG-PPG-PEG/Dexamethasone (PLA/F68/ Dex) implant prepared by HME has been developed. Importantly, the implant was successfully achieved to control release of immunosuppressive drug to an implanted device. In particular, this implant has not been reported previously in pharmaceutical fields. FTIR and XRD were adopted to investigate the properties of the samples. The in vivo release study showed that the maximum value of Dex release from the implants was approximately 50% at 1 month. The in vivo degradation behavior was determined by UV spectrophotometer and scanning electron microscopy studies, and the weight loss rate of the implants were up to 25% at 1 month. Furthermore, complete blood count (CBC) test, serum chemistry and major organs were performed, and there is no significant lesion and side effects observed in these results. Therefore, the results elucidated that the new PLA/F68/Dex implant prepared by HME could deliver an immunosuppressive drug to control the inflammatory reaction at the implant site.

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The anti-inflammatory potency of dexamethasone is determined by the route of application in vivo

Cited by 14 publications

References 17 publications

Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells

Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells

Lipopolysaccharide Renders Transgenic Mice Expressing Human Serum Amyloid P Component Sensitive to Shiga Toxin 2

PLA/PEG-PPG-PEG/Dexamethasone implant prepared by hot-melt extrusion for controlled release of immunosuppressive drug to implantable medical devices, part 2:in vivoevaluation

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