HMG-CoA Reductase Inhibitor Simvastatin Inhibits Proinflammatory Cytokine Production from Murine Mast Cells

Kagami, Shin-ichiro; Kanari, Hiroko; Suto, Akira; Fujiwara, Michio; Ikeda, Kei; Hirose, Koichi; Watanabe, Norihiko; Iwamoto, Itsuo; Nakajima, Hiroshi

doi:10.1159/000126063

Cited by 25 publications

(16 citation statements)

References 48 publications

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“…Wang, Song, Wang, Chen, & Yan, 2013), mast cells (Kagami, et al, 2008), T-cells (Ghittoni, et al, 2005; Samson, et al, 2005; Shibata, et al, 2002; Shimada, Park, & Daida, 2006; Yamashita, et al, 1999) and dendritic cells (Yilmaz, et al, 2006) are all affected by HMGCR activity and MVA pathway metabolites and/or GTPases. Even given this limited sampling of a larger body of scientific work, this evidence collectively indicates a foundational role for the MVA pathway in respiratory health and disease.…”

Section: Pulmonary Diseasementioning

confidence: 99%

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

Yeganeh

Wiechec

Ande

et al. 2014

Pharmacology & Therapeutics

139

129

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The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs (‘statins’) directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD), and cancer.

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Section: Pulmonary Diseasementioning

confidence: 99%

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

Yeganeh

Wiechec

Ande

et al. 2014

Pharmacology & Therapeutics

139

129

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“…Research on statins is no longer limited to investigating the lipid lowering effects, with an increasing number of studies investigating the anti-inflammatory effects. Due to the anti-inflammatory effects, statins can inhibit the release of inflammatory factors, thus, statins may exert effects on the inflammatory response against sepsis (33,34). Chello et al (35) used cecal ligation and puncture (CLP) to generate a rat model of sepsis.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin increases lipopolysaccharide-induced expression of tumour necrosis factor-α-induced protein 8-like 2 in RAW264.7 cells

Liu

Zhang

et al. 2014

Experimental and Therapeutic Medicine

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RAW264.7 cells are one of the major sources of productive inflammatory biomediators, including tumour necrosis factor-α (TNF-α) and interleukin (IL)-6. TNF-α-induced protein 8-like 2 (TIPE2) is an essential negative regulator of Toll-like and T-cell receptors, and the selective expression in the immune system prevents hyper-responsiveness and maintains immune homeostasis. The aim of the present study was to investigate whether atorvastatin upregulates the expression of TIPE2 and further regulates the inflammatory response and oxidation emergency response in RAW264.7 cells. RAW264.7 cells were incubated in Dulbecco’s modified Eagle’s medium containing lipopolysaccharide (LPS) in the presence or absence of atorvastatin. Following incubation, the medium was collected and the levels of TNF-α and IL-6 were measured using an enzyme-linked immunosorbent assay. The cells were harvested, and the mRNA and protein expression levels of TIPE2, macrophage migration inhibitory factor (MIF), IκB and nuclear factor (NF-κB)-κB were analysed using quantitative polymerase chain reaction and western blotting analysis, respectively, the expression of NOS, COX-2 and HO-1 protein were essayed by western blotting analysis, NO and ROS activities were determined. The results revealed that LPS increased the mRNA and protein expression levels of TIPE2, MIF and NF-κB, as well as the production of IL-6 and TNF-α, in a dose and time dependent manner in RAW264.7 cells. Meanwhile, LPS enhanced the expression of NOS and COX-2 protein, blocked HO-1 protein expression, increased NO and PGE2 production and ROS activity in a dose dependent manner in RAW264.7 cells. Atorvastatin significantly increased LPS induced expression of TIPE2, downregulated the expression of NOS, COX-2, MIF and NF-κB and the production of PGE2, NO, IL-6 and TNF-α in a time and dose dependent manner, and increased HO-1 protein expression, reduced ROS production in a dose dependent manner. The observations indicated that atorvastatin upregulated LPS induced expression of TIPE2 and consequently inhibited MIF, NF-κB, NOS and COX-2 expression and the production of NO, PGE2, TNF-α and IL-6, increased HO-1 expression, and inhibited ROS activity in cultured RAW264.7 cells.

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“…For example, direct ASM-MC interaction promotes MC survival and proliferation, induces MC degranulation that is allergen-independent (67), and stimulates ASM differentiation to the contractile phenotype by an autocrine mechanism involving TGFβ (66). Moreover, simvastatin inhibited the production of TNF-α and IL-6 from mouse activated MC (68). Interestingly, cerivastatin, atorvastatin, lovastatin to a lesser extend but not simvastatin or pravastatin inhibit growth and function of human MC (69).…”

Section: Targeting the Airway Smooth Muscle: Statins As Potential Medmentioning

confidence: 99%

Targeting the airway smooth muscle for asthma treatment

Camoretti-Mercado¹

2009

Translational Research

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Asthma is a complex respiratory disease whose incidence has increased worldwide in the last decade. There is currently no cure for asthma. While bronchodilator and anti-inflammatory medications are effective medicines in some asthmatic patients, it is clear that an unmet therapeutic need persists for a subpopulation of individuals with severe asthma. This chronic lung disease is characterized by airflow limitation and lung inflammation and remodeling that includes increased airway smooth muscle (ASM) mass. In addition to its contractile properties, the ASM also contributes to the inflammatory process by producing active mediators, modifying the extracellular matrix composition, and interacting with inflammatory cells. These undesirable functions make interventions aimed at reducing ASM abundance an attractive strategy for novel asthma therapies. There are at least three mechanisms that could limit the accumulation of smooth muscle -decreased cell proliferation, augmented cell apoptosis, and reduced cell migration into the smooth muscle layer. Inhibitors of the mevalonate pathway or statins hold promise for asthma because they exhibit antiinflammatory, anti-migratory, and anti-proliferative effects in pre-clinical and clinical studies, and they can target the SM. This review will discuss current knowledge of ASM biology and identify gaps in the field in order to stimulate future investigations of the cellular mechanisms controlling ASM overabundance in asthma. Targeting ASM has the potential to be an innovative venue of treatment for patients with asthma. Keywordsairway smooth muscle; asthma; contractile; cytokine; hyperplasia; hypertrophy; inflammation; mevalonate; progenitor cells; statins; TGF beta; translational The Smooth Muscle in Lung Diseases: An Overlooked Target for TherapyThe majority of the smooth muscle present in the human lung localizes within two major compartments, the vasculature and the airways. The function of the pulmonary vascular smooth muscle (VSM) in maintaining appropriate gas exchange is well established. The peristaltic activity of the ASM is known to contribute to the normal branching of the respiratory tree during lung embryogenesis (1) (2). While ASM plays a central role in regulating the airway caliber, the real function of the ASM in the adult lung remains unclear and controversial. It has Send Correspondence to:

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HMG-CoA Reductase Inhibitor Simvastatin Inhibits Proinflammatory Cytokine Production from Murine Mast Cells

Cited by 25 publications

References 48 publications

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

Atorvastatin increases lipopolysaccharide-induced expression of tumour necrosis factor-α-induced protein 8-like 2 in RAW264.7 cells

Targeting the airway smooth muscle for asthma treatment

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