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Hexabromocyclododecane and tetrabromobisphenol A alter secretion of interferon gamma (IFN-?) from human immune cells.

ABSTRACT: Hexabromocyclododecane (HBCD) and tetrabromobisphenol A (TBBPA) are brominated flame-retardant compounds used in a variety of applications including insulation, upholstery, and epoxy resin circuit boards. Interferon gamma (IFN-?) is an inflammatory cytokine produced by activated T and NK cells that regulates immune responsiveness. HBCD and TBBPA are found in human blood, and previous studies have shown that they alter the ability of human natural killer (NK) lymphocytes to destroy tumor cells. This study examines whether HBCD and TBBPA affect the secretion of IFN-? from increasingly complex preparations of human immune cells-purified NK cells, monocyte-depleted (MD) peripheral blood mononuclear cells (PBMCs), and PBMCs. Both HBCD and TBBPA were tested at concentrations ranging from 0.05 to 5 µM. HBCD generally caused increases in IFN-? secretion after 24-h, 48-h, and 6-day exposures in each of the different cell preparations. The specific concentration of HBCD that caused increases as well as the magnitude of the increase varied from donor to donor. In contrast, TBBPA tended to decrease secretion of IFN-? from NK cells, MD-PBMCs, and PBMCs. Thus, exposure to these compounds may potentially disrupt the immune regulation mediated by IFN-?. Signaling pathways that have the capacity to regulate IFN-? production (nuclear factor kappa B (NF-?B), p44/42, p38, JNK) were examined for their role in the HBCD-induced increases in IFN-?. Results showed that the p44/42 (ERK1/2) MAPK pathway appears to be important in HBCD-induced increases in IFN-? secretion from human immune cells.

SUBMITTER: Almughamsi H

PROVIDER: S-EPMC4767696 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Hexabromocyclododecane and tetrabromobisphenol A alter secretion of interferon gamma (IFN-γ) from human immune cells.

Almughamsi Haifa H Whalen Margaret M MM

Archives of toxicology 20150825 7

Hexabromocyclododecane (HBCD) and tetrabromobisphenol A (TBBPA) are brominated flame-retardant compounds used in a variety of applications including insulation, upholstery, and epoxy resin circuit boards. Interferon gamma (IFN-γ) is an inflammatory cytokine produced by activated T and NK cells that regulates immune responsiveness. HBCD and TBBPA are found in human blood, and previous studies have shown that they alter the ability of human natural killer (NK) lymphocytes to destroy tumor cells. T ...[more]

PMID: 26302867

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Project description:Evaluation of antigen-specific T-cell responses to viral antigens is frequently performed on IFN-? secreting cells. However, T-cells are capable of producing many more functions than just IFN-?, some of which, like Perforin, are associated with immune protection in HIV-1 disease elite controllers. We evaluated the extent of missed T-cell functions when IFN-? secretion is used as a surrogate marker for further evaluation of T-cell functions. Intracellular cytokine staining assay and flow cytometry were used to assess peripheral blood mononuclear cells (PBMCs) from 31 HIV-infected ART-naive individuals for the extent to which gated CD4+ and CD8+ IFN-? producing and non-producing T-cells also secreted IL-2, Perforin, and TNF-? functions. Similarly, the extent of missed virus-specific responses in IFN-? ELISpot assay negative T-cells from 5 HIV-1 uninfected individuals was evaluated. Cells from HIV-infected individuals were stimulated with pooled consensus group M (Con M) peptides; and those from healthy individuals were stimulated with pooled adenovirus (Ad) peptides. Overall, frequencies of virus-specific IFN-? secreting CD4+ and CD8+ cells were low. Proportions of IFN-? negative CD4+ expressing IL-2, Perforin, or TNF-? to Con M were significantly higher (5 of 7 functional profiles) than the corresponding IFN-? positive CD4+ (0 of 7) T-cell phenotype, p?=?0.02; Fisher's Exact test. Likewise, proportions of CD8+ T-cells expressing other functions were significantly higher in 4 of the 7 IFN-? negative CD8+ T-cells. Notably, newly stimulated Perforin, identified as Perforin co-expression with IL-2 or TNF-?, was significantly higher in IFN-? negative CD8+ T-cell than in the positive CD8+ T-cells. Using SEB, lower responses in IFN-? positive cells were most associated with CD4+ than CD8+ T-cells. These findings suggest that studies evaluating immunogenicity in response to HIV and Adenovirus viral antigens should not only evaluate T-cell responsiveness among IFN-? producing cells but also among those T-cells that do not express IFN-?.

Project description:BackgroundSurfactant proteins are produced predominantly by alveolar type II (ATII) cells, and the expression of these proteins can be altered by cytokines and growth factors. Th1/Th2 cytokine imbalance is suggested to be important in the pathogenesis of several adult lung diseases. Recently, we developed a culture system for maintaining differentiated adult human ATII cells. Therefore, we sought to determine the effects of IL-13 and IFN-γ on the expression of surfactant proteins in adult human ATII cells in vitro. Additional studies were done with rat ATII cells.MethodsAdult human ATII cells were isolated from deidentified organ donors whose lungs were not suitable for transplantation and donated for medical research. The cells were cultured on a mixture of Matrigel and rat-tail collagen for 8 d with differentiation factors and human recombinant IL-13 or IFN-γ.ResultsIL-13 reduced the mRNA and protein levels of surfactant protein (SP)-C, whereas IFN-γ increased the mRNA level of SP-C and proSP-C protein but not mature SP-C. Neither cytokine changed the mRNA level of SP-B but IFN-γ slightly decreased mature SP-B. IFN-γ reduced the level of the active form of cathepsin H. IL-13 also reduced the mRNA and protein levels of SP-D, whereas IFN-γ increased both mRNA and protein levels of SP-D. IL-13 did not alter SP-A, but IFN-γ slightly increased the mRNA levels of SP-A.ConclusionsWe demonstrated that IL-13 and IFN-γ altered the expression of surfactant proteins in human adult ATII cells in vitro. IL-13 decreased SP-C and SP-D in human ATII cells, whereas IFN-γ had the opposite effect. The protein levels of mature SP-B were decreased by IFN-γ treatment, likely due to the reduction in active form cathepsin H. Similarly, the active form of cathepsin H was relatively insufficient to fully process proSP-C as IFN-γ increased the mRNA levels for SP-C and proSP-C protein, but there was no increase in mature SP-C. These observations suggest that in disease states with an overexpression of IL-13, there would be some deficiency in mature SP-C and SP-D. In disease states with an excess of IFN-γ or therapy with IFN-γ, these data suggest that there might be incomplete processing of SP-B and SP-C.

Dataset Information

Hexabromocyclododecane and tetrabromobisphenol A alter secretion of interferon gamma (IFN-?) from human immune cells.

Publications

Hexabromocyclododecane and tetrabromobisphenol A alter secretion of interferon gamma (IFN-γ) from human immune cells.

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