Inhibition of IFN-γ responses in human choriocarcinoma cells by PTPs (166.18)

Abstract

Abstract Placental trophoblast cells (TBCs) form the fetal component of the placenta, and are the only blastocyst-derived cells in direct contact with maternal blood and thus immune system. Interferon-γ (IFN-γ) is a pro-inflammatory cytokine that is critical for the activation of both innate and adaptive immune responses, inhibition of cell proliferation, and induction of apoptosis. Interestingly, IFN-γ is present in the uterus during normal pregnancy and levels can be further enhanced upon intrauterine infection. Despite the presence of IFN-γ in the uterus, human TBCs do not express either MHC class Ia or class II antigens and are resistant to IFN-γ-mediated apoptosis. We previously demonstrated that TBCs are hypo-responsive to IFN-γ due to protein tyrosine phosphatase (PTP)-mediated inhibition of the JAK-STAT-1 pathway. These results suggest that inhibition of IFN-γ signaling in TBCs is due to differential regulation of PTP activity. In most cell types, PTPs are constitutively active and are transiently inactivated by reactive oxygen species that are generated in response to ligand binding. Our current studies suggest that SHP-2 and/or PTP-1B are responsible for inhibiting IFN-γ responses in human TBCs. Moreover, our data demonstrate that human TBC-derived choriocarcinoma cells produce H2O2 in response to IFN-γ. Furthermore, studies in which TBCs were exposed to exogenous H2O2 or antioxidants suggest that lack of H2O2 production is not the basis for differential PTP activity.