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.
Abstract-Several prospective clinical studies have indicated that hydroxymethylglutaryl-coenzyme A reductase inhibitors, statins, prevent cardiovascular events in part through their antiinflammatory properties. Because inflammation is positively and negatively regulated by T helper (Th) 1 cells and Th2 cells, respectively, we examined the effects of statins on the Th polarization in vitro and in vivo. Here we demonstrated that the statins tested, ie, cerivastatin, simvastatin, lovastatin, and atorvastatin, promoted Th2 polarization through both inhibition of Th1 development and augmentation of Th2 development of CD4 ϩ T cells primed in vitro with anti-CD3 antibody and splenic antigen-presenting cells. Cerivastatin exerted most potent effect on modulation of Th1/Th2 development, and the effect was completely abrogated by an addition of mevalonate. Consistent with in vitro experiments, cerivastatin treatment decreased IFN-␥ production of lymph node cells from mice immunized with ovalbumin emulsified in complete Freund's adjuvant, indicating that Th1 development is also suppressed in an in vivo proinflammatory environment. In this murine model, cerivastatin significantly reduced mesangial matrix expansion of glomeruli in the kidney and attenuated proteinuria. The decrease of glomerular sclerosis by cerivastatin treatment was positively related to the suppression of interferon (IFN)-␥-producing Th1 response in draining lymph node cells. Hence, these findings strongly suggest that statins' inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase regulates Th1/Th2 polarization in vivo and such a mechanism possibly plays a pathophysiological role in immune-related glomerular injury.
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