Inhibition of Hydroxymethylglutaryl-Coenzyme a Reductase Reduces Th1 Development and Promotes Th2 Development

Hakamada-Taguchi, Rie; Uehara, Yoshio

doi:10.1097/00004872-200402001-00179

Cited by 50 publications

(63 citation statements)

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“…Therefore, it is possible that EDC might not suppress Th1-type immune responses. However, the possibility seems unlikely, since we have previously shown that hydroxymethylglutaryl-coenzyme A reductase inhibitors, statins, suppressed Th1-type immunity via suppression of Th1 development with concomitant increase in the generation of Th0 cells [20].…”

Section: P<001) These Results Suggest That Edc Might Exacerbate Airmentioning

confidence: 99%

Endocrine disruptors that deplete glutathione levels in APC promote Th2 polarization in mice leading to the exacerbation of airway inflammation

et al. 2006

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Endocrine‐disrupting chemicals (EDC) are ubiquitous in environment and may have various undesirable effects on human health. In the present study, we have shown that some EDC [benzophenone, p‐octylphenol, and tributyltin chloride (TBT)] promoted strong Th2 polarization via suppression and augmentation of Th1 and Th2 development, respectively, from naive CD4+ T cells primed with anti‐CD3 and splenic antigen‐presenting cells (APC). The effect was indicated to be indirect via suppression of IL‐12 production and augmentation of IL‐10 production of APC, which are critical for the Th1 and Th2 development, respectively. Such modulation of cytokine production by EDC was associated with reduction of intracellular glutathione levels in APC. IL‐10 deprivation or the addition of N‐acetylcysteine, which replenishes intracellular glutathione level during priming, cancelled the effect of EDC on the promotion of Th2 polarization. Oral administration of TBT, which most effectively promoted Th2 polarization in vitro, exacerbated airway inflammation in a murine model of allergic asthma with concomitant enhancement of Th2‐type immunity. Collectively these results suggest that EDC such as benzophenone, p‐octylphenol, and TBT promote Th2 polarization indirectly via the depletion of glutathione in APC and subsequent modulation of IL‐10 and IL‐12 production that might result in the exacerbation of allergic diseases.

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Section: P<001) These Results Suggest That Edc Might Exacerbate Airmentioning

confidence: 99%

Endocrine disruptors that deplete glutathione levels in APC promote Th2 polarization in mice leading to the exacerbation of airway inflammation

et al. 2006

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“…Accumulated evidence has indicated that atherogenesis is initiated by the interplay between cholesterol metabolism and cellular secretion of various cytokines. 23 Cholesterol lowering might have an immune modulation in the equilibrium between sub-populations of T-helper cells 24 and improve endothelial function, 25 and cholesterol accumulation is considered to be associated with an inappropriate immune response to vascular injury. 25 Our data suggest that monocyte cholesterol homeostasis was disturbed in our hypertensive patients because of the reduction of ABC transporters, which might potentially influence the function of monocytes and initiate vascular injury in these hypertensive patients.…”

Section: Discussionmentioning

confidence: 99%

The expression of ATP-binding cassette transporters in hypertensive patients

Zhou

et al. 2009

Hypertens Res

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Cholesterol efflux is regulated by cholesterol transporters, including adenosine triphosphate-binding cassette transporters, A1, G1 (ABCA1, ABCG1), and scavenger receptor class B type I (SR-BI). We have investigated whether the expression of these transporters/receptor is altered in patients with hypertension and also studied their functional effects in cholesterol efflux. The newly diagnosed hypertensive patients, as well as age-and gender-matched healthy controls were recruited. mRNA of ABCA1, ABCG1 and SR-BI in monocytes was measured. The functional effects of the three transporters/receptor and cholesterol efflux from monocyte-derived macrophages ex vivo were also determined. The expression of ABCA1 and ABCG1 was significantly decreased in the newly diagnosed untreated hypertensive patients compared with that in healthy controls. The levels of ABCA1 and ABCG1 were negatively associated with blood pressure, and the reduction of ABCA1 and ABCG1 could be reversed by antihypertensive therapy. No significant associations between plasma lipids, oxidized low-density lipoprotein (LDL) and the expression of ABCA1 or ABCG1 were found. Cholesterol efflux from monocyte-derived macrophages to autologous serum, apolipoprotein AI (apoAI) or high-density lipoprotein (HDL) was impaired in hypertensive patients. Cholesterol efflux to autologous serum or apoAI was associated with the expression of ABCA1, whereas cholesterol efflux to autologous serum or HDL was associated with the expression of ABCG1. The expression of ABCA1 and ABCG1 in monocytes is reduced in hypertensive patients, which could be reversed by anti-hypertensive therapy. The reduction in ABCA1/ABCG1 is associated with the impairment of cholesterol efflux from monocyte-derived macrophages.

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“…Statins inhibit T-cell activation, cell cycle progression and proliferation, as well as migration, both through an HMG-CoA-reductase-independent mechanism, involving allosteric inhibition of LFA-1 [3] and HMGCoA-reductase-dependent mechanisms, which rely on their capacity to inhibit prenylation of small GTPases [4,5]. Moreover, recent reports have provided evidence that some statins also affect helper T-cell differentiation by promoting Th2 polarization and suppressing Th1 polarization both in vitro and in vivo [6,7]. This activity highlights statins as potential drugs in the treatment of diseases dominated by Th1 responses.…”

Section: Introductionmentioning

confidence: 99%

“…affect helper T-cell differentiation by promoting Th2 polarization and suppressing Th1 polarization both in vitro and in vivo [6,7]. This activity highlights statins as potential drugs in the treatment of diseases dominated by Th1 responses.…”

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confidence: 96%

Simvastatin impairs humoral and cell‐mediated immunity in mice by inhibiting lymphocyte homing, T‐cell activation and antigen cross‐presentation

et al. 2008

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Statins block the activity of HMG-CoA reductase, which catalyses the production of mevalonate, an intermediate in cholesterol biosynthesis, which is also a precursor of isoprenoids. In addition to lowering circulating cholesterol, these drugs display antiinflammatory and immunomodulatory activities in vitro; however, their effects on the development of adaptive immune responses in vivo, as well as the underlying mechanisms, are as yet largely unknown. Here we investigated the outcome of simvastatin treatment on a number of processes, which together orchestrate adaptive immunity to specific antigen. Simvastatin treatment resulted in a marked reduction of T and B cells in spleen, lymph nodes and peripheral blood in mice. This effect could be ascribed principally to an impairment of lymphocyte homing to secondary lymphoid organs. In addition, simvastatin was found to strongly inhibit T-cell responses to the MHCI restricted hen ovalbumin peptide antigen SIINFEKL and to impair ovalbumin uptake and cross-presentation by MHCI. Simvastatin also suppressed antibody responses to immunization with ovalbumin and delayed-type hypersensitivity to allergens. These activities could be largely accounted for by the simvastatin-dependent inhibition of HMG-CoA reductase. The data provide novel mechanistic insight into the activities of simvastatin in the highly complex context of the immune response.Key words: Apoptosis . Homing . Immune responses . Simvastatin IntroductionStatins are competitive inhibitors of HMG-CoA reductase, a major rate-limiting enzyme that controls HMG-CoA conversion to mevalonic acid in the cholesterol biosynthetic pathway. In addition to lowering circulating cholesterol, statins act as antiinflammatory and immunomodulatory agents [1]. These activities have been largely ascribed to their capacity to block isoprenoid production, and thereby to inhibit prenylation of small Ras superfamily GTPases, which are master regulators of cell activation and proliferation, cytoskeletal remodelling and membrane trafficking [2].Statins suppress T-cell activation both directly and by interfering with APC maturation and function. Statins inhibit T-cell activation, cell cycle progression and proliferation, as well as migration, both through an HMG-CoA-reductase-independent mechanism, involving allosteric inhibition of LFA-1 [3] and HMGCoA-reductase-dependent mechanisms, which rely on their capacity to inhibit prenylation of small GTPases [4,5]. Moreover, recent reports have provided evidence that some statins also 2832affect helper T-cell differentiation by promoting Th2 polarization and suppressing Th1 polarization both in vitro and in vivo [6,7]. This activity highlights statins as potential drugs in the treatment of diseases dominated by Th1 responses. Statins have been indeed shown to prevent or reverse several Th1-mediated autoimmune conditions in mice, such as autoimmune encephalomyelitis [8], spontaneous systemic lupus erythematosus [9,10], autoimmune myocarditis [11] and autoimmune retinal disease [12] via suppressio...

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Inhibition of Hydroxymethylglutaryl-Coenzyme a Reductase Reduces Th1 Development and Promotes Th2 Development

Cited by 50 publications

References 0 publications

Endocrine disruptors that deplete glutathione levels in APC promote Th2 polarization in mice leading to the exacerbation of airway inflammation

Endocrine disruptors that deplete glutathione levels in APC promote Th2 polarization in mice leading to the exacerbation of airway inflammation

The expression of ATP-binding cassette transporters in hypertensive patients

Simvastatin impairs humoral and cell‐mediated immunity in mice by inhibiting lymphocyte homing, T‐cell activation and antigen cross‐presentation

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