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

Abstract

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.

Thioredoxin suppresses airway inflammation independently of systemic Th1/Th2 immune modulation

“…In previous studies, we showed that oxidative stress promotes the development of Th2 type immune responses via induction of Th2 cell differentiation and Th1 cell apoptosis, which ultimately exacerbate Th2-driven airway inflammation [10,28]. TRX along with GSH constitutes a major reducing system that protects the host from oxidative stress.…”

“…This imbalance is though to contribute to asthma in part through activation of redox-sensitive transcription factor NF-kB in epithelial cells and subsequent production of eotaxin, which further promotes eosinophil infiltration into the lung [7][8][9]. In addition to the proinflammatory effects of ROS in the potentiation of asthmatic reactions in the lung, the oxidant/antioxidant imbalance in the draining LN contributes to the initiation of Th2 type immunity via induction of Th2 cell differentiation [10][11][12][13]. Thus the oxidant/ antioxidant imbalance plays an important role in both the development and the progression of asthma pathogenesis [14].…”

Differential Regulatory Function of Resting and Preactivated Allergen-Specific CD4+CD25+ Regulatory T Cells in Th2-Type Airway Inflammation

“…challenge with OVA. Twenty-four hours after the last challenge, we performed bronchoalveolar lavage of lethally anesthetized mice as described previously (19,20). Bronchoalveolar lavage fluid (BALF) supernatant was stored at Ϫ30°C until assayed for cytokines by ELISA.…”

“…IL-4, IL-5, IL-10, and IFN-␥ levels in culture supernatants or BALF were assayed by ELISA as described (19,21). The lower detection limits of these assays were 6 pg/ml (IL-4), 50 pg/ml (IL-5), 100 pg/ml (IFN-␥), and 24 pg/ml (IL-10).…”

Recent developments in the role of reactive oxygen species in allergic asthma

“…Glutathione can also affect cellular signaling through regulation of redox sensitivity, transcription factors and phosphatases (89,90). Furthermore, glutathione levels can be decreased due to several environment pollutants that have been linked to increased asthma prevalence worldwide (70,91). Glutathione attenuated AHR and inflammation could occur through several mechanisms: (I) the Th1/Th2 balance (70); (II) alteration of NO metabolism through the formation of S-nitrosoglutathione, which was reported to be associated with regulation of airway responses (59); and (III) altering the balance between ROS inhibition and antioxidant reaction (55).…”