Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • PD PD L signaling is critical for the induction of

    2021-09-18

    PD-1/PD-L1 signaling is critical for the induction of exhausted CD8+ T SB 225002 during the tumor immune response (Barber et al., 2006; Wherry et al., 2007; Wherry and Kurachi,2015; Pauken and Wherry, 2015), but the relationship between PD-1/PD-L1 signaling and Fas/FasL signaling in exhausted CD8+ T cells remains unclear. PD-1 reduces T cell survival by preventing the expression of the antiapoptotic gene Bcl-xL through the inhibition of PI3K activation during T cell activation (Parry et al., 2005) and by up-regulating the proapoptotic factor Bim (Gibbons et al., 2012). It has also been reported that the expression of PD-L1 in tumor cells increases apoptosis of activated tumor-reactive T cells, resulting in the induction of tumor growth (Dong et al., 2002). Here, we found that the expression of Fas and FasL were up-regulated in activated T cells after TCR-mediated activation upon stimulation of PD-L1 in the tumor cells, indicating that the interaction between Fas and FasL may be a component of the PD-L1-mediated apoptosis of activated T cells. Thus, the combined blockade of both Fas and PD-L1 signaling in the locale of the tumor may induce the survival of exhausted CD8+ T cells and thus prove useful for cancer immunotherapy.
    Conflicts of interest
    Acknowledgements We thank Dr. Shigeo Koyasu for providing Bcl-2 transgenic mice. This work was supported by the Grant-in-Aid for Scientific Research, the Japanese Ministry of Education, Culture, Sports, Science and Technology [grant numbers: 20591542 and 16K10450].
    Introduction Despite being one of the leading causes of maternal death and a major contributor to maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of HELLP (Hemolysis, Elevated Liver enzymes, Low Platelet) syndrome remain unclear [1], [2]. HELLP syndrome is becoming more recognized as an immune based disease, as studies by our labs and others have reported increased circulating and placental levels of inflammatory cytokines and anti-angiogenic imbalance [3], [4], [5]. The Fas receptor and FasL (Fas Ligand) are part of the TNF receptor family and have multiple roles, including regulation of an inflammatory response via activation and proliferation of CD4+ T lymphocytes [6], [7]. Under physiologic conditions, FasL will bind Fas+ cells to induce apoptosis or activate CD4+ T cells. However dysregulation of the Fas/FasL system leads to a decrease in Fas activation and may result in autoimmune and chronic inflammatory diseases [8], [9]. While there is evidence of dysregulation of the Fas/FasL system in pregnancies complicated with hypertension such as HELLP syndrome, the reason or effect of this dysfunction is unclear [10], [11]. Fas/FasL has not been reported to have a direct role in the induction of hypertension, however when this system is left unchecked then apoptosis of inflammatory cytokine secreting leukocytes can become decreased. As leukocytes have been implicated in inducing not only inflammation but also endothelial activation and hypertension [12], [13], [14], it is important to determine the role of Fas/FasL in contributing to this phenomenon. Pharmacological blockade of the endothelin system during pregnancy has been demonstrated to attenuate hypertension [12], [15], [16], which points to the importance of the endothelin system in women who suffer from hypertensive pregnancies. We have recently reported a role of the endothelin system in mediating the hypertension, increased CD4+ T cells and the biochemistry that defines HELLP syndrome in an experimental animal model of HELLP [16]. Interestingly, alteration of the Fas pathway has been shown to lead to endothelial cell activation and vascular dysfunction [17], [18], [19]. Therefore in the current study we sought to determine if rats experiencing hypertension, inflammation and endothelin activation in response to a HELLP-like syndrome had alterations in Fas/FasL respective to normal pregnant rats. We also wanted to determine if blockade of the endothelin system altered any HELLP-induced changes in Fas/FasL expression.