scholarly journals HPTE-Induced Embryonic Thymocyte Death and Alteration of Differentiation Is Not Rescued by ERα or GPER Inhibition but Is Exacerbated by Concurrent TCR Signaling

2021 ◽  
Vol 22 (18) ◽  
pp. 10138
Author(s):  
Eddie Avellaneda ◽  
Atalie Lim ◽  
Sara Moeller ◽  
Jacqueline Marquez ◽  
Priscilla Escalante Cobb ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Adverse Effects ◽  
Endocrine Disrupting Chemicals ◽  
Cell Receptor ◽  
Endocrine Function ◽  
Tcr Signaling ◽  
Primary Metabolite ◽  
Signaling Mechanism ◽  
Receptor Inhibition ◽  
Er Alpha

Organochlorine pesticides, such as DDT, methoxychlor, and their metabolites, have been characterized as endocrine disrupting chemicals (EDCs); suggesting that their modes of action involve interaction with or abrogation of endogenous endocrine function. This study examined whether embryonic thymocyte death and alteration of differentiation induced by the primary metabolite of methoxychlor, HPTE, rely upon estrogen receptor binding and concurrent T cell receptor signaling. Estrogen receptor inhibition of ERα or GPER did not rescue embryonic thymocyte death induced by HPTE or the model estrogen diethylstilbestrol (DES). Moreover, adverse effects induced by HPTE or DES were worsened by concurrent TCR and CD2 differentiation signaling, compared with EDC exposure post-signaling. Together, these data suggest that HPTE- and DES-induced adverse effects on embryonic thymocytes do not rely solely on ER alpha or GPER but may require both. These results also provide evidence of a potential collaborative signaling mechanism between TCR and estrogen receptors to mediate adverse effects on embryonic thymocytes, as well as highlight a window of sensitivity that modulates EDC exposure severity.

scholarly journals The different effects of endocrine-disrupting chemicals on estrogen receptor-mediated transcription through interaction with coactivator TRAP220 in uterine tissue

2003 ◽  
Vol 31 (3) ◽  
pp. 551-561 ◽  
Author(s):  
H Inoshita ◽  
H Masuyama ◽  
Y Hiramatsu
Keyword(s):  
Estrogen Receptor ◽  
Bisphenol A ◽  
Endocrine Disrupting Chemicals ◽  
Endocrine Function ◽  
Uterine Tissue ◽  
Present Evidence ◽  
Endocrine Disrupting Chemical ◽  
Positive Effects ◽  
Endocrine Disrupting

An endocrine-disrupting chemical (EDC) can alter endocrine functions through a variety of mechanisms, including nuclear receptor-mediated changes in protein synthesis, interference with membrane receptor binding, steroidogenesis or synthesis of other hormones. Although major chemicals have been shown to disrupt estrogenic actions mainly through their binding to estrogen receptor (ER) or androgen receptor, it is not clear how EDCs affect endocrine functions in vivo. We present evidence that the EDCs bisphenol A and phthalate activate ER-mediated transcription through interaction with TRAP220. Moreover, bisphenol A had positive effects on the interaction between ER-beta and TRAP220 and on the expression of ER-beta and TRAP220 compared with phthalate and estradiol in uterine tIssue. These data suggested that some EDCs might alter endocrine function through the change of the receptor and coactivator levels in uterine tIssue and through the different effect on the interaction between ERs and coactivator TRAP220.

scholarly journals Targeting CAR to the Peptide-MHC Complex Reveals Distinct Signaling Compared to That of TCR in a Jurkat T Cell Model

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 867
Author(s):  
Ling Wu ◽  
Joanna Brzostek ◽  
Shvetha Sankaran ◽  
Qianru Wei ◽  
Jiawei Yap ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Model ◽  
Cell Receptor ◽  
Target Cells ◽  
Tcr Signaling ◽  
Barr Virus ◽  
Car T ◽  
Epstein Barr ◽  
Lower Magnitude

Chimeric antigen receptor T cells (CAR-T) utilize T cell receptor (TCR) signaling cascades and the recognition functions of antibodies. This allows T cells, normally restricted by the major histocompatibility complex (MHC), to be redirected to target cells by their surface antigens, such as tumor associated antigens (TAAs). CAR-T technology has achieved significant successes in treatment of certain cancers, primarily liquid cancers. Nonetheless, many challenges hinder development of this therapy, such as cytokine release syndrome (CRS) and the efficacy of CAR-T treatments for solid tumors. These challenges show our inadequate understanding of this technology, particularly regarding CAR signaling, which has been less studied. To dissect CAR signaling, we designed a CAR that targets an epitope from latent membrane protein 2 A (LMP2 A) of the Epstein–Barr virus (EBV) presented on HLA*A02:01. Because of this, CAR and TCR signaling can be compared directly, allowing us to study the involvement of other signaling molecules, such as coreceptors. This comparison revealed that CAR was sufficient to bind monomeric antigens due to its high affinity but required oligomeric antigens for its activation. CAR sustained the transduced signal significantly longer, but at a lower magnitude, than did TCR. CD8 coreceptor was recruited to the CAR synapse but played a negligible role in signaling, unlike for TCR signaling. The distinct CAR signaling processes could provide explanations for clinical behavior of CAR-T therapy and suggest ways to improve the technology.

scholarly journals Ca2+/Calmodulin-Dependent Protein Kinase II Is a Modulator of CARMA1-Mediated NF-κB Activation

2006 ◽  
Vol 26 (14) ◽  
pp. 5497-5508 ◽  
Author(s):  
Kazuhiro Ishiguro ◽  
Todd Green ◽  
Joseph Rapley ◽  
Heather Wachtel ◽  
Cosmas Giallourakis ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Dependent Protein Kinase ◽  
Immune Synapse ◽  
Protein Kinase Ii ◽  
Dependent Protein

ABSTRACT CARMA1 is a central regulator of NF-κB activation in lymphocytes. CARMA1 and Bcl10 functionally interact and control NF-κB signaling downstream of the T-cell receptor (TCR). Computational analysis of expression neighborhoods of CARMA1-Bcl10MALT 1 for enrichment in kinases identified calmodulin-dependent protein kinase II (CaMKII) as an important component of this pathway. Here we report that Ca2+/CaMKII is redistributed to the immune synapse following T-cell activation and that CaMKII is critical for NF-κB activation induced by TCR stimulation. Furthermore, CaMKII enhances CARMA1-induced NF-κB activation. Moreover, we have shown that CaMKII phosphorylates CARMA1 on Ser109 and that the phosphorylation facilitates the interaction between CARMA1 and Bcl10. These results provide a novel function for CaMKII in TCR signaling and CARMA1-induced NF-κB activation.

scholarly journals Effects of the Hedgehog signalling inhibitor itraconazole on developing rat ovaries

2021 ◽  
Author(s):  
Hanna Katarina Lilith Johansson ◽  
Camilla Taxvig ◽  
Gustav Peder Mohr Olsen ◽  
Terje Svingen
Keyword(s):  
Endocrine Disrupting Chemicals ◽  
Endocrine Disrupting Compounds ◽  
Perinatal Period ◽  
Endocrine Function ◽  
Ovary Development ◽  
Knock Out ◽  
Female Reproductive Health ◽  
Endocrine Disrupting ◽  
Hh Signaling ◽  
Knock Out Mice

Abstract Early ovary development is considered to be largely hormone independent, yet there are associations between fetal exposure to endocrine disrupting chemicals and reproductive disorders in women. This can potentially be explained by perturbations to establishment of ovarian endocrine function rather than interference with an already established hormone system. In this study we explore if Hedgehog (HH) signaling, a central pathway for correct ovary development, can be disrupted by exposure to HH-disrupting chemicals, using the antifungal itraconazole as model compound. In the mouse Leydig cell line TM3, used as a proxy for ovarian theca cells, itraconazole exposure had a suppressing effect on genes downstream of HH signaling, such as Gli1. Exposing explanted rat ovaries (gestational day 22 or postnatal day 3) to 30 µM itraconazole for 72 h induced significant suppression of genes in the HH signaling pathway with altered Ihh, Gli1, Ptch1, and Smo expression similar to those previously observed in Ihh/Dhh knock-out mice. Exposing rat dams to 50 mg/kg bw/day in the perinatal period did not induce observable changes in the offspring’s ovaries. Overall, our results suggest that HH signal disruptors may affect ovary development with potential long-term consequences for female reproductive health. However, potent HH inhibitors would likely cause severe teratogenic effects at doses lower than those causing ovarian dysgenesis, so the concern with respect to reproductive disorder is for the presence of HH disruptors at low concentration in combination with other ovary or endocrine disrupting compounds.

scholarly journals Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor–mediated immune responses but not in TCR signaling

2007 ◽  
Vol 204 (5) ◽  
pp. 1013-1024 ◽  
Author(s):  
Tatsukata Kawagoe ◽  
Shintaro Sato ◽  
Andreas Jung ◽  
Masahiro Yamamoto ◽  
Kosuke Matsui ◽  
...  
Keyword(s):  
Immune Responses ◽  
Kinase Activity ◽  
Interleukin 1 ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
Toll Like Receptor ◽  
Tcr Signaling ◽  
Mitogen Activated Protein

Interleukin-1 receptor–associated kinase 4 (IRAK-4) was reported to be essential for the Toll-like receptor (TLR)– and T cell receptor (TCR)–mediated signaling leading to the activation of nuclear factor κB (NF-κB). However, the importance of kinase activity of IRAK family members is unclear. In this study, we investigated the functional role of IRAK-4 activity in vivo by generating mice carrying a knockin mutation (KK213AA) that abrogates its kinase activity. IRAK-4KN/KN mice were highly resistant to TLR-induced shock response. The cytokine production in response to TLR ligands was severely impaired in IRAK-4KN/KN as well as IRAK-4−/− macrophages. The IRAK-4 activity was essential for the activation of signaling pathways leading to mitogen-activated protein kinases. TLR-induced IRAK-4/IRAK-1–dependent and –independent pathways were involved in early induction of NF-κB–regulated genes in response to TLR ligands such as tumor necrosis factor α and IκBζ. In contrast to a previous paper (Suzuki, N., S. Suzuki, D.G. Millar, M. Unno, H. Hara, T. Calzascia, S. Yamasaki, T. Yokosuka, N.J. Chen, A.R. Elford, et al. 2006. Science. 311:1927–1932), the TCR signaling was not impaired in IRAK-4−/− and IRAK-4KN/KN mice. Thus, the kinase activity of IRAK-4 is essential for the regulation of TLR-mediated innate immune responses.

scholarly journals Regulation of proximal T cell receptor signaling and tolerance induction by deubiquitinase Usp9X

2014 ◽  
Vol 211 (10) ◽  
pp. 1947-1955 ◽  
Author(s):  
Edwina Naik ◽  
Joshua D. Webster ◽  
Jason DeVoss ◽  
Jinfeng Liu ◽  
Rowena Suriben ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tolerance Induction ◽  
Ubiquitin Ligases ◽  
Cell Receptor ◽  
Lymphoproliferative Disease ◽  
Deubiquitinating Enzymes ◽  
Tcr Signaling ◽  
Self Tolerance ◽  
A Cell

The T cell hyperproliferation and autoimmune phenotypes that manifest in mice lacking E3 ubiquitin ligases such as Cbl, ITCH, or GRAIL highlight the importance of ubiquitination for the maintenance of peripheral T cell tolerance. Less is known, however, about the deubiquitinating enzymes that regulate T cell proliferation and effector function. Here, we define a cell intrinsic role for the deubiquitinase Usp9X during proximal TCR signaling. Usp9X-deficient T cells were hypoproliferative, yet mice with T cell–specific Usp9x deletion had elevated numbers of antigen-experienced T cells and expanded PD-1 and OX40-expressing populations consistent with immune hyperactivity. Aged Usp9x KO mice developed lupus-like autoimmunity and lymphoproliferative disease, indicating that ubiquitin ligases and deubiquitinases maintain the delicate balance between effective immunity and self-tolerance.

scholarly journals Differential activation by xenoestrogens of ER alpha and ER beta when linked to different response elements

1998 ◽  
Vol 158 (3) ◽  
pp. R11-R14 ◽  
Author(s):  
WD Pennie ◽  
TC Aldridge ◽  
AN Brooks
Keyword(s):  
Estrogen Receptor ◽  
Luteinizing Hormone ◽  
Molecular Basis ◽  
Estrogen Response Element ◽  
Differential Activation ◽  
Response Elements ◽  
Estrogen Response ◽  
Cell Tissue ◽  
Different Response ◽  
Er Alpha

The discovery of a second estrogen receptor (ER beta) has significant implications for our understanding of the molecular basis for the diverse actions of estrogen. Here we report the differential activation by natural and xenobiotic estrogens of ER alpha and ER beta when linked to different response elements. Receptor mediated activation of reporter constructs containing either the estrogen response element (ERE) from the vitellogenin (Vit) gene or from the luteinizing hormone beta (LH) gene were examined in transiently transfected Cos-1 cells. ER beta preferentially activated the consensus Vit ERE whereas ER alpha showed greater activation at the divergent LH ERE. This differential activation was observed for a number of ligands including estradiol, estrone, bisphenol A, octylphenol and diethystilbestrol. These findings show that the nature of the ERE, as well as the ratio of ER subtypes in a particular cell/tissue, will influence whether particular estrogen responsive genes are activated in the presence of natural or xenobiotic estrogens.

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