Dietary phosphatidylinositol protects C57BL/6 mice from concanavalin A-induced liver injury by modulating immune cell functions

2013 ◽  
Vol 57 (9) ◽  
pp. 1671-1679 ◽  
Author(s):  
Masashi Inafuku ◽  
Koji Nagao ◽  
Ayako Inafuku ◽  
Teruyoshi Yanagita ◽  
Naoyuki Taira ◽  
...  
Keyword(s):  
Liver Injury ◽  
Concanavalin A ◽  
Immune Cell ◽  
Cell Functions

scholarly journals PARP2 deficiency affects invariant-NKT-cell maturation and protects mice from concanavalin A-induced liver injury

2017 ◽  
Vol 313 (5) ◽  
pp. G399-G409 ◽  
Author(s):  
Aveline Filliol ◽  
Claire Piquet-Pellorce ◽  
Sarah Dion ◽  
Valentine Genet ◽  
Catherine Lucas-Clerc ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Liver Injury ◽  
Concanavalin A ◽  
Immune Cell ◽  
Cell Populations ◽  
Genetic Inactivation ◽  
Hepatocyte Death ◽  
Invariant Natural Killer ◽  
Deficient Mice ◽  
Nkt Lymphocytes

Excessive or persistent inflammation and hepatocyte death are the key triggers of liver diseases. The poly(ADP-ribose) polymerase (PARP) proteins induce cell death and inflammation. Chemical inhibition of PARP activity protects against liver injury during concanavalin A (ConA)-induced hepatitis. In this mice model, ConA activates immune cells, which promote inflammation and induce hepatocyte death, mediated by the activated invariant natural killer T (iNKT) lymphocyte population. We analyzed immune cell populations in the liver and several lymphoid organs, such as the spleen, thymus, and bone marrow in Parp2-deficient mice to better define the role of PARP proteins in liver immunity and inflammation at steady state and during ConA-induced hepatitis. We show that 1) the genetic inactivation of Parp2, but not Parp1, protected mice from ConA hepatitis without deregulating cytokine expression and leucocyte recruitment; 2) cellularity was lower in the thymus, but not in spleen, liver, or bone marrow of Parp2−/− mice; 3) spleen and liver iNKT lymphocytes, as well as thymic T and NKT lymphocytes were reduced in Parp2 knockout mice. In conclusion, our results suggest that the defect of T-lymphocyte maturation in Parp2 knockout mice leads to a systemic reduction of iNKT cells, reducing hepatocyte death during ConA-mediated liver damage, thus protecting the mice from hepatitis. NEW & NOTEWORTHY The genetic inactivation of Parp2, but not Parp1, protects mice from concanavalin A hepatitis. Immune cell populations are lower in the thymus, but not in the spleen, liver, or bone marrow of Parp2-deficient mice compared with wild-type mice. Spleen and liver invariant natural killer T (NKT) lymphocytes, as well as thymic T and NKT lymphocytes, are reduced in Parp2-deficient mice.

WISP1 modulates immune cell infiltration upon drug-induced liver injury (DILI)

2015 ◽  
Vol 53 (12) ◽  
Author(s):  
AB Widera ◽  
L Pütter ◽  
S Leserer ◽  
G Campos ◽  
K Rochlitz ◽  
...  
Keyword(s):  
Liver Injury ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Drug Induced ◽  
Drug Induced Liver Injury

The role of microbiota in concanavalin A-mediated liver injury

2018 ◽  
Vol 56 (01) ◽  
pp. E2-E89
Author(s):  
B Schiller ◽  
C Wegscheid ◽  
L Berkhout ◽  
A Zarzycka ◽  
U Steinhoff ◽  
...  
Keyword(s):  
Liver Injury ◽  
Concanavalin A

scholarly journals Jagged1-mediated myeloid Notch1 signaling activates HSF1/Snail and controls NLRP3 inflammasome activation in liver inflammatory injury

2019 ◽  
Vol 17 (12) ◽  
pp. 1245-1256 ◽  
Author(s):  
Yuting Jin ◽  
Changyong Li ◽  
Dongwei Xu ◽  
Jianjun Zhu ◽  
Song Wei ◽  
...  
Keyword(s):  
Liver Injury ◽  
Inflammatory Response ◽  
Immune Cell ◽  
Ischemia Reperfusion ◽  
Inflammasome Activation ◽  
Inflammatory Injury ◽  
Notch1 Signaling ◽  
Caspase 1 ◽  
Hepatocellular Damage ◽  
Hepatocellular Apoptosis

AbstractNotch signaling plays important roles in the regulation of immune cell functioning during the inflammatory response. Activation of the innate immune signaling receptor NLRP3 promotes inflammation in injured tissue. However, it remains unknown whether Jagged1 (JAG1)-mediated myeloid Notch1 signaling regulates NLRP3 function in acute liver injury. Here, we report that myeloid Notch1 signaling regulates the NLRP3-driven inflammatory response in ischemia/reperfusion (IR)-induced liver injury. In a mouse model of liver IR injury, Notch1-proficient (Notch1FL/FL) mice receiving recombinant JAG1 showed a reduction in IR-induced liver injury and increased Notch intracellular domain (NICD) and heat shock transcription factor 1 (HSF1) expression, whereas myeloid-specific Notch1 knockout (Notch1M-KO) aggravated hepatocellular damage even with concomitant JAG1 treatment. Compared to JAG1-treated Notch1FL/FL controls, Notch1M-KO mice showed diminished HSF1 and Snail activity but augmented NLRP3/caspase-1 activity in ischemic liver. The disruption of HSF1 reduced Snail activation and enhanced NLRP3 activation, while the adoptive transfer of HSF1-expressing macrophages to Notch1M-KO mice augmented Snail activation and mitigated IR-triggered liver inflammation. Moreover, the knockdown of Snail in JAG1-treated Notch1FL/FL livers worsened hepatocellular functioning, reduced TRX1 expression and increased TXNIP/NLRP3 expression. Ablation of myeloid Notch1 or Snail increased ASK1 activation and hepatocellular apoptosis, whereas the activation of Snail increased TRX1 expression and reduced TXNIP, NLRP3/caspase-1, and ROS production. Our findings demonstrated that JAG1-mediated myeloid Notch1 signaling promotes HSF1 and Snail activation, which in turn inhibits NLRP3 function and hepatocellular apoptosis leading to the alleviation of IR-induced liver injury. Hence, the Notch1/HSF1/Snail signaling axis represents a novel regulator of and a potential therapeutic target for liver inflammatory injury.

scholarly journals DDRE-09. DEVELOPING IDO-PROTACS TO IMPROVE IMMUNOTHERAPEUTIC EFFICACY IN PATIENTS WITH GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii63-ii63
Author(s):  
Lakshmi Bollu ◽  
Derek Wainwright ◽  
Lijie Zhai ◽  
Erik Ladomersky ◽  
Kristen Lauing ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Time Course ◽  
Immune Cell ◽  
Enzyme Inhibitors ◽  
Tumor Development ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Specific Protein ◽  
Cell Functions

Abstract INTRODUCTION Indoleamine 2,3-dioxygenase 1 (IDO; IDO1) is a rate-limiting enzyme that metabolizes the essential amino acid tryptophan into kynurenine. Recent work by our group has revealed that IDO promotes tumor development and suppresses immune cell functions independent of its enzyme activity. Moreover, pharmacologic IDO enzyme inhibitors that currently serve as the only class of drugs available for targeting immunosuppressive IDO activity, fail to improve the survival of patients with GBM. Here, we developed IDO-Proteolysis Targeting Chimeras (IDO-PROTACs). PROTACs bind to a specific protein and recruit an E3 ubiquitin ligase that enhance proteasome-mediated degradation of the target protein. METHODS A library of ≥100 IDO-PROTACs were developed by joining BMS986205 (IDO binder) with a linker group to various E3-ligase ligands. Western blot analysis of PROTAC-induced IDO degradation was tested in vitro among multiple human and mouse GBM cell lines including U87, GBM6, GBM43 and GL261 along a time course ranging between 1–96 hours of treatment and at varying concentrations. The mechanism of IDO protein degradation was investigated using pharmacologic ligands that inhibit or compete with the proteasome-mediated protein degradation pathway. RESULTS Primary screening identified several IDO-PROTACs with IDO protein degradation potential. Secondary screening showed that our lead compound has a DC50 value of ~0.5µM with an ability to degrade IDO in all GBM cells analyzed, and an initial activity within 12 hours of treatment that extended for up to 96 hours. Mutating the CRBN-binding ligand, pretreatment with the ubiquitin proteasome system inhibitors MG132 or MLN4924 or using unmodified parental compound all inhibited IDO protein degradation. CONCLUSIONS This study developed an initial IDO-PROTAC technology that upon further optimization, can neutralize both IDO enzyme and non-enzyme immunosuppressive effects. When combined with other forms of immunotherapy, IDO-PROTACs have the potential to substantially enhance immunotherapeutic efficacy in patients with GBM.

Dregea volubilisAmeliorates Concanavalin A-Induced Liver Injury by Facilitating Apoptosis of Activated T Cells

2008 ◽  
Vol 233 (9) ◽  
pp. 1124-1132 ◽  
Author(s):  
Fangyuan Gong ◽  
Yan Shen ◽  
Chaofeng Zhang ◽  
Jianliang Xu ◽  
Xuefeng Wu ◽  
...  
Keyword(s):  
T Cells ◽  
Liver Injury ◽  
Concanavalin A ◽  
Activated T Cells

A phase Ib study of the PI3Kδ inhibitor linperlisib in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3099-3099
Author(s):  
Jin Li ◽  
Nong Xu ◽  
Tianshu Liu ◽  
Jianjin Huang ◽  
Yongmei Yin ◽  
...  
Keyword(s):  
Disease Control ◽  
Solid Tumors ◽  
Immune Cell ◽  
Target Lesion ◽  
Advanced Solid Tumors ◽  
Cell Functions ◽  
Potential Clinical Benefit ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

3099 Background: Phosphatidylinositol-3 kinase (PI3K) pathways are important elements of tumor survival and progression, and PIK3C genes are often mutated or overexpressed in many cancers. Additionally, PIK3D (PI3Kδ) modulates immune cell functions in tumors, elaborating another PI3Kδ inhibition feature with a potential clinical benefit. Linperlisib, an oral and highly selective PI3Kδ inhibitor, demonstrated potent anti-tumor activity in syngeneic animals from previous research. In this Phase 1b study, the safety, tolerability, and efficacy of linperlisib is under investigation for patients with advanced solid tumors. Methods: Linperlisib was given orally once daily (QD) in 28-day cycle until disease progression, unacceptable toxicity, or withdrawal from the study. Adverse events (AEs) were graded by NCI-CTCAE v5.0. Efficacy was assessed according to RECIST1.1 criteria. Results: As of December 28, 2020, 70 patients were enrolled in the Phase1b study, with advanced cancers, including colorectal (n = 22), breast (n = 8), lung (n = 8), kidney (n = 5), liver (n = 4), ovarian (n = 1), head and neck (n = 5), and esophageal (n = 1) cancers; sarcomas, (n = 4), small intestinal stromal tumor (n = 3), thymic (n = 2), gallbladder (n = 2), gastric (n = 4), and pancreatic (n = 1) carcinomas. The patients were heavily pretreated with an average of 4 previous lines of therapy. Among the 70 patients, the most common nonhematologic TEAEs (all grades/grade≥3) were proteinuria (37.14%/0%), elevated aspartate aminotransferase (20%/0%), nausea (20%/0%), oral mucositis (2.8%/2.8%), diarrhea (2.8%/2.8%). The most common hematological TEAEs were leukopenia (24.28%/0%) and neutropenia (17.14%/4.28%). There were no unexpected toxicities in this study. Of 42 patients evaluable for response, the overall response rate was 2.38%. Notably, the disease control rate (DCR) was 45.24% from monotherapy treatment. One patient with thymic carcinoma obtained a partial response (80.8% reduction of the target lesion), with a duration of response of more than 6 cycles. The treatment of this subject is continuing. A lung adenocarcinoma subject reached radiological stable disease associated with 13.7% reduction in the target lesion and disease control for approximately 6 months. Conclusions: In this study, the PI3K inhibitor, linperlisib exhibited a favorable safety profile as was previously seen in lymphoma patients. Monotherapy treatment with linperlisib was observed to impart a high DCR in advanced solid cancers of many types. Available data from linperlisib and other PI3K inhibitors suggests that linperlisib may limit tumor growth directly, but also by affecting the tumor immune microenvironment. With these promising indications of clinical tolerability and activity, further investigation of linperlisib alone or in key therapeutic combinations is warranted. Clinical trial information: NCT04049929.

scholarly journals Fucosterol Protects against Concanavalin A-Induced Acute Liver Injury: Focus on P38 MAPK/NF-κB Pathway Activity

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Wenhui Mo ◽  
Chengfen Wang ◽  
Jingjing Li ◽  
Kan Chen ◽  
Yujing Xia ◽  
...  
Keyword(s):  
Liver Injury ◽  
P38 Mapk ◽  
Concanavalin A ◽  
Molecular Mechanisms ◽  
Therapeutic Agent ◽  
Acute Liver Injury ◽  
Biological Activities ◽  
Hepatic Necrosis ◽  
Protective Effects ◽  
Eisenia Bicyclis

Objective. Fucosterol is derived from the brown alga Eisenia bicyclis and has various biological activities, including antioxidant, anticancer, and antidiabetic properties. The aim of this study was to investigate the protective effects of fucosterol pretreatment on Concanavalin A- (ConA-) induced acute liver injury in mice, and to understand its molecular mechanisms. Materials and Methods. Acute liver injury was induced in BALB/c mice by ConA (25 mg/kg), and fucosterol (dissolved in 2% DMSO) was orally administered daily at doses of 25, 50, and 100 mg/kg. The levels of hepatic necrosis, apoptosis, and autophagy associated with inflammatory cytokines were measured at 2, 8, and 24 h. Results. Fucosterol attenuated serum liver enzyme levels and hepatic necrosis and apoptosis induced by TNF-α, IL-6, and IL-1β. Fucosterol also inhibited apoptosis and autophagy by upregulating Bcl-2, which decreased levels of functional Bax and Beclin-1. Furthermore, reduced P38 MAPK and NF-κB signaling were accompanied by PPARγ activation. Conclusion. This study showed that fucosterol could alleviate acute liver injury induced by ConA by inhibiting P38 MAPK/PPARγ/NF-κB signaling. These findings highlight that fucosterol is a promising potential therapeutic agent for acute liver injury.

scholarly journals Regulation of Gastrointestinal Immunity by Metabolites

2020 ◽  
Author(s):  
Bon-Hee Gu ◽  
Myunghoo Kim ◽  
Cheol-Heui Yun
Keyword(s):  
Gastrointestinal Tract ◽  
Immune Cell ◽  
Underlying Mechanism ◽  
Intestinal Immunity ◽  
Surface Receptors ◽  
Functional Activities ◽  
Cell Functions ◽  
Dietary Antigens ◽  
Molecular Regulatory Mechanisms ◽  
Microbial Enzymatic Activities

The gastrointestinal tract contains multiple types of immune cells that maintain the balance between tolerance and activation at the first line of host defense facing non-self antigens, including dietary antigens, commensal bacteria, and sometimes unexpected pathogens. Maintaining homeostasis at the gastrointestinal tract requires stringent regulation of the immune responses against various environmental conditions. Diet can be converted into gut metabolites which have unique functional activities through host as well as microbial enzymatic activities. Accumulating evidences demonstrate that gastrointestinal metabolites have significant impacts on the regulation of intestinal immunity and further integrate immune response of distal mucosal tissue. Metabolites, especially derived from microbiota, regulate immune cell functions by various ways including recognition and activation of cell surface receptors, controlling of gene expression by epigenetic regulation and integration of cellular metabolism. These mucosal immune regulations are key to understand underlying mechanism for the development of gastrointestinal disorders. Here, we review the recent advancement of our understanding on the role of gut metabolites in the regulation of gastrointestinal immunity with highlighting the cellular and molecular regulatory mechanisms by macronutrients-derived metabolites.

425 In-vitro regulation of immune cell functions by human IgE

1991 ◽  
Vol 87 (1) ◽  
pp. 246
Author(s):  
R PARHAR ◽  
P ERNST ◽  
F ALMOHANNA ◽  
A KWAASI ◽  
K SHETH ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Functions
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