[Show abstract][Hide abstract] ABSTRACT: CD4(+) T cells are critical for adaptive immunity. MAP4K4 is a key member of germinal center kinase group. However, the physiological function of MAP4K4 in primary CD4(+) T cells is still unclear. In this study, it was demonstrated that in vitro, MAP4K4 deletion remarkably suppressed CD4(+) T cell proliferation in response to phorbol 12-myristate 13-acetate (PMA) and ionomycin, which was not due to enhancing cell apoptosis. Additionally, MAP4K4 was required for the activation of CD4(+) T cells. MAP4K4 deletion significantly down-regulated expression of interleukin 2 (IL-2) and interferon-γ (IFN-γ), while notably up-regulating the expression of regulatory T cells (Treg) transcription factor Foxp3 in peripheral CD4(+) T cells. Furthermore, western blot analysis indicated that CD4(+) T cells lacking MAP4K4 failed to phosphorylate Jnk, Erk, p38 and PKC-θ. Thus, our results provide the evidence that MAP4K4 is essential for CD4(+) T cell proliferation, activation and cytokine production.
Full-text · Article · Mar 2014 · Cellular Immunology
[Show abstract][Hide abstract] ABSTRACT: The potential developmental toxicity of environmental estrogenic endocrine disruptors have become a great concern in recent years. In this study, two typical environmental oestrogen, namely, bisphenol A (BPA) and genistein (GEN) were investigated for potential embryotoxicity using the embryonic stem cell test model. Afterwards, a 4×4 full factorial design and the estimated marginal means plot were performed to assess the combined effects of these two compounds. According to the linear discriminant functions and classification criteria, bisphenol A and genistein were classified as weakly embryotoxic and strongly embryotoxic respectively. As for combined effects, the overall interaction between BPA and GEN on embryonic stem cells (ESCs) differentiation was synergistic at low dosages, however, on ESCs and 3T3 cell proliferation, the predominate action was additive. Considering the actual daily intake of these chemicals, it is concluded that BPA alone might not have adverse reproductive or developmental effects on human being. However, given that BPA and GEN do have synergistic effect at low concentration, they may disturb normal embryo development together, which could result in birth defect and behavioral alterations later in life.
No preview · Article · Aug 2013 · Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association
[Show abstract][Hide abstract] ABSTRACT: Bisphenol A (BPA) has been widely used in the manufacture of polycarbonate plastic, water bottles and food containers. Previous studies have established that BPA could cause developmental toxicity by inhibiting the proliferation and differentiation of rat embryonic midbrain (MB) cells in vitro. However, the underlying mechanisms have not been well studied yet. In the current study, we examined the proliferation and differentiation of MB cells treated with 10(-12)-10(-4) M BPA and found that only 10(-4) M BPA inhibited proliferation and differentiation. Then, we investigated the cell cycle progression and apoptosis of MB cells; 10(-4) M BPA caused an explicit S phase and G2/M phase arrest in the cell cycle and increased the percentage of apoptotic cells. Moreover, the phosphorylation of mitogen-activated protein kinase (MAPK) and cyclic-AMP response binding protein (CREB) and the expression of some apoptotic regulatory genes were investigated. BPA (10(-4) M) reduced the phosphorylation of C-Jun N-terminal kinase (JNK) and CREB, and increased the mRNA expression level of Bax and p53. Our findings demonstrated that BPA could cause developmental toxicity through anti-proliferation and pro-apoptosis in MB cells. Multiple signaling pathways, such as the JNK, CREB and p53- mitochondrial apoptosis pathways, participate in these effects.
No preview · Article · Nov 2012 · Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association
[Show abstract][Hide abstract] ABSTRACT: Bisphenol A (BPA) is an environmental estrogen that exhibits non-genotoxic carcinogenicity, causing concern globally. The aim was to investigate the effects of BPA on the proliferation and cell cycle of human normal breast cells HBL-100. An improved E-Screen assay was used to study cell proliferation, and flow cytometry was used to study cell cycle phases. Western blot analysis was utilized to detect cell cycle proteins and estrogen receptor α (ERα) expression. The results showed that the highest cell proliferation rate induced by BPA was at 1.0 × 10(-6)mol/L. At 1.0 × 10(-10), 1.0 × 10(-8), and 1.0 × 10(-6)mol/L, BPA promoted more cells to enter into G2/M phase and caused an increase in the expression of cyclinD1 and CDK4. After adding ICI182780 into the system, the promoting effects of BPA on cell proliferation and cell cycle change decreased, but these promoting effects were still significantly greater compared with the solvent control (P<0.05). Regardless of ICI182780 exposure, BPA did not have significant effect on ERα expression. BPA has estrogen-like activity and can stimulate HBL-100 proliferation and cell division through the estrogen receptor pathway. BPA may have other pathways through which it can exert stimulating effects and exhibit non-genotoxic carcinogenicity.
No preview · Article · Jun 2012 · Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association
[Show abstract][Hide abstract] ABSTRACT: Some studies show that Cd(2+) and Hg(2+) may induce cell proliferation and apoptosis via biphasic dose-response relationship in human cells. However, mechanisms underlying this phenomenon are still in puzzle. In this study, we aim at detecting the biphasic effects of Cd(2+) and Hg(2+) on proliferation and apoptosis of human embryonic kidney 293 (HEK293) cells, analyzing the change of the mitogen-activated protein kinase (MAPK) pathways, and discussing the relationship between them. The results demonstrate that Cd(2+) and Hg(2+) can stimulate cell proliferation at lower concentrations (0.05 and 0.5 microM) but inhibit it at higher concentrations (50 and 500 microM). Apoptosis increases at higher concentrations (50 and 500 microM) of Cd(2+) and Hg(2+). While 0.5 microM Cd(2+) and Hg(2+) decrease the JNK phosphorylation, 50 microM Cd(2+) and Hg(2+) increase the JNK and P38 phosphorylation. When HEK293 cells are treated with 20 microM JNK inhibitor or 100 microM ERK1/2 inhibitor, the cell proliferation do not increase significantly at low concentrations (0.05 and 0.5 microM), but still decrease at high concentrations (50 and 500 microM). When HEK293 cells are treated with 20 microM P38 inhibitor, the tendency of cell proliferation is not affected. Data in our study suggests that activation of MAPK pathway may be involved in the biphasic effect induced by Cd(2+) and Hg(2+).
Preview · Article · Apr 2009 · Toxicology in Vitro