Fluvastatin and lovastatin inhibit granulocyte macrophage–colony stimulating factor‐stimulated human eosinophil adhesion to inter‐cellular adhesion molecule‐1 under flow conditions

Robinson, Arthur C.; Kashanin, Dmitry; O'Dowd, Frank; Fitzgerald, Kate D.; Williams, Vivienne; Walsh, Garry Michael

doi:10.1111/j.1365-2222.2009.03334.x

Cited by 30 publications

(23 citation statements)

References 41 publications

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“…Although fluvastatin exerted antiinflammatory effects (IL-8) in both cell lines, our data show that this was not mediated by the induction of A20 (mRNA), clearly confirming the sscMap prediction. In asthma, fluvastatin inhibits eosinophil adhesion to ICAM-1 (39) and fibroblast proliferation (40). Using similar concentrations, we did not observe any reduced proliferation.…”

Section: Discussionmentioning

confidence: 63%

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Malcomson

Wilson

Veglia

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cystic fibrosis (CF) lung disease is characterized by chronic and exaggerated inflammation in the airways. Despite recent developments to therapeutically overcome the underlying functional defect in the cystic fibrosis transmembrane conductance regulator, there is still an unmet need to also normalize the inflammatory response. The prolonged and heightened inflammatory response in CF is, in part, mediated by a lack of intrinsic down-regulation of the proinflammatory NF-κB pathway. We have previously identified reduced expression of the NF-κB down-regulator A20 in CF as a key target to normalize the inflammatory response. Here, we have used publicly available gene array expression data together with a statistically significant connections' map (sscMap) to successfully predict drugs already licensed for the use in humans to induce A20 mRNA and protein expression and thereby reduce inflammation. The effect of the predicted drugs on A20 and NF-κB(p65) expression (mRNA) as well as proinflammatory cytokine release (IL-8) in the presence and absence of bacterial LPS was shown in bronchial epithelial cells lines (16HBE14o−, CFBE41o−) and in primary nasal epithelial cells from patients with CF (Phe508del homozygous) and non-CF controls. Additionally, the specificity of the drug action on A20 was confirmed using cell lines with tnfαip3 (A20) knockdown (siRNA). We also show that the A20-inducing effect of ikarugamycin and quercetin is lower in CF-derived airway epithelial cells than in non-CF cells.A20 | NF-κB | connectivity mapping | drug repositioning | CF airway inflammation

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Section: Discussionmentioning

confidence: 63%

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Malcomson

Wilson

Veglia

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…There are also reports that human eosinophils can process and present antigen to activate specific T cells, (20) but, again, it remains to be established how widespread is such ability in different individuals and for different antigens. Despite the evidence that eosinophils have the potential to act as APC to drive Th cell responses and thereby propagate inflammation, (21,22) other findings have suggested that this is limited to super-antigens and peptides, rather than proteins that require processing. (11,16) The effects of Th activation are critically dependent on the subset(s) that respond, and the associated cytokines they produce, but it is not known whether eosinophil antigen presentation preferentially supports responses by any particular Th type.…”

Section: Introductionmentioning

confidence: 99%

“…(22) Briefly, eosinophils and CD4 + Th cells were removed from co-culture, washed and saturating quantities of primary antibodies or specific isotype controls were added to the cells and incubated for 40 min at 4 0 C in the dark, washed and fixed.…”

Section: Immunostaining and Flow Cytometrymentioning

confidence: 99%

“…All subjects gave informed consent and the study was approved by the North of Scotland Research Ethics Service (ref 09/S0801/16). Eosinophils were purified from samples of peripheral blood using our standard technique (22) using dextran sedimentation and centrifugation on Percoll gradients followed by CD16-dependent negative immunomagnetic selection. To obtain CD4 + Th cells, peripheral blood mononuclear cells (PBMC) were isolated by density gradient centrifugation (23) and non-target cells depleted by negative selection following the manufacturer's instructions.…”

Section: Eosinophil and Th Cell Isolationmentioning

confidence: 99%

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Effective antigen presentation to helper T cells by human eosinophils

et al. 2016

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Although eosinophils are inflammatory cells, there is increasing attention on their immunomodulatory roles. For example, murine eosinophils can present antigen to CD4+ T helper (Th) cells, but it remains unclear whether human eosinophils also have this ability. This study determined whether human eosinophils present a range of antigens, including allergens, to activate Th cells, and characterized their expression of MHC class II and co-stimulatory molecules required for effective presentation.Human peripheral blood eosinophils purified from non-allergic donors were pulsed with the antigens house dust mite extract (HDM), Timothy Grass extract (TG) or Mycobacterium tuberculosis purified protein derivative (PPD), before co-culture with autologous CD4+ Th cells. Proliferative and cytokine responses were measured, with eosinophil expression of HLA-DR/DP/DQ and the co-stimulatory molecules CD40,

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“…Fluvastatin and lovastatin inhibited the adhesion of human eosinophils to recombinant human intercellular adhesion molecule-1, and this effect was reversed by the addition of mevalonate [43] . In addition, pravastatin and fluvastatin reduced the expression of intercellular adhesion molecule-1 and the release of TNF-α, IFN-γ and IL-12 from cultured human peripheral blood mononuclear cells [43] . In recent years, it has been suggested that the accumulation of eosinophils in asthma could be due to their prolonged survival and defective apoptosis [44,45] .…”

Section: Pharmacological Targets Of Statins In Asthmamentioning

confidence: 99%

Statins in Asthma: A Closer Look into the Pharmacological Mechanism of Action

Al‐Sawalha

Knoll

2016

Pharmacology

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The effect of stains in asthma is mediated through targeting several signaling molecules that are involved in the development of asthma phenotype. In vitro and in vivo studies revealed that statins reduce airway smooth muscle cells proliferation and inflammatory mediators' release. Statins reduce chemokine release and mucus production from airway epithelial cells besides attenuating subepithelial fibrosis and eosinophils recruitment. In acute and chronic allergen driven animal models of asthma, statins reduce airway hyper-responsiveness, inflammation and remodeling. However, the effectiveness of statins in clinical trials results in contradictory conclusions based on study design and treatment protocol. Therefore, more clinical trials are needed to evaluate their role in asthma patients.

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Fluvastatin and lovastatin inhibit granulocyte macrophage–colony stimulating factor‐stimulated human eosinophil adhesion to inter‐cellular adhesion molecule‐1 under flow conditions

Abstract: Inhibition of eosinophil adhesion to ICAM-1 by fluvastatin and lovastatin under physiological shear stress represent novel actions by these drugs that may inform the development of anti-inflammatory therapy for allergic disease.

Cited by 30 publications

References 41 publications

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Effective antigen presentation to helper T cells by human eosinophils

Statins in Asthma: A Closer Look into the Pharmacological Mechanism of Action

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