Short-form Ron receptor is required for normal IFN-γ production in concanavalin A-induced acute liver injury

2007 ◽  
Vol 292 (1) ◽  
pp. G253-G261 ◽  
Author(s):  
Cynthia C. Wetzel ◽  
Mike A. Leonis ◽  
Arlene Dent ◽  
Meredith A. Olson ◽  
Angela M. Longmeier ◽  
...  
Keyword(s):  
Liver Injury ◽  
Concanavalin A ◽  
Inflammatory Responses ◽  
Acute Liver Injury ◽  
Ex Vivo ◽  
Short Form ◽  
Cell Receptor ◽  
Ron Receptor ◽  
Ifn Γ

Abrogation of Ron receptor tyrosine kinase function results in defects in macrophage activation and dysregulated acute inflammatory responses in vivo. Several naturally occurring constitutively active alternative forms of Ron have been identified, including from primary human tumors and tumor cell lines. One of these alternative forms, short-form (SF) Ron, is generated from an alternative start site in intron 10 of the Ron gene that eliminates most of the extracellular portion of the receptor and is overexpressed in several human cancers. To test the physiological significance of SF-Ron in vivo, mice were generated that solely express the full-length form of Ron (FL-Ron). Our results show that elimination of the capacity to express SF-Ron in vivo leads to augmented production of IFN-γ from splenocytes following stimulation ex vivo with either concanavalin A or anti-CD3/T cell receptor monoclonal antibody. Moreover, in a concanavalin A-induced murine model of acute liver injury, FL-Ron mice have increased production of serum INF-γ and serum alanine aminotransferase levels and worsened liver histology and overall survival compared with wild-type control mice. Taken together, these results suggest for the first time that SF-Ron impacts the progression of inflammatory immune responses in vivo and further support a role for the Ron receptor and its various forms in liver pathophysiology.

scholarly journals In vivo siRNA delivery of Keap1 modulates death and survival signaling pathways and attenuates concanavalin-A-induced acute liver injury in mice

2014 ◽  
Vol 7 (9) ◽  
pp. 1093-1100 ◽  
Author(s):  
A. Gonzalez-Rodriguez ◽  
B. Reibert ◽  
T. Amann ◽  
R. Constien ◽  
C. M. Rondinone ◽  
...  
Keyword(s):  
Liver Injury ◽  
Signaling Pathways ◽  
Concanavalin A ◽  
Acute Liver Injury ◽  
Sirna Delivery ◽  
Survival Signaling

scholarly journals IL-22 ameliorates LPS-induced acute liver injury by autophagy activation through ATF4-ATG7 signaling

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Lujing Shao ◽  
Xi Xiong ◽  
Yucai Zhang ◽  
Huijie Miao ◽  
Yuqian Ren ◽  
...  
Keyword(s):  
Liver Injury ◽  
Inflammatory Responses ◽  
Acute Liver Injury ◽  
Mrna Levels ◽  
Protective Effects ◽  
Activating Transcription Factor 4 ◽  
Pre Treatment ◽  
Underlying Mechanisms

Abstract Uncontrollable inflammatory response acts as a driver of sepsis-associated liver injury (SALI). IL-22 plays an important role in regulating inflammatory responses, but its role in SALI remains unknown. The aim of the study was to assess the association of serum IL-22 with SALI in pediatric patients and to enclose the underlying mechanisms of IL-22 involved in lipopolysaccharide (LPS) - induced acute liver injury (ALI) in mice. Serum IL-22 levels in patients with SALI were significantly lower than in septic patients without liver injury, and the area under receiver operating characteristic (ROC) curve of IL-22 for discriminating SALI was 0.765 (95% CI: 0.593–0.937). Pre-administration of recombinant murine IL-22 alleviated LPS-induced ALI in mice, and serum IL-6 levels and the mRNA levels of TNF-α, IL-1β, and IL-6 in livers were decreased in response to IL-22 pre-treatment in mice. More importantly, IL-22 pre-treatment activated hepatic autophagy mediated by activating transcription factor 4 (ATF4)-autophagy-related gene 7 (ATG7) signaling in vivo and in vitro in response to LPS administration. Moreover, knockdown of ATF4 in mice aggravated LPS-induced ALI, which was associated with suppressed ATG7-related autophagy. In addition, the protective effects of IL-22 on LPS-induced ALI was partially blocked by ATF4 knockdown, which was associated with lower expression of LC3II/I in the livers of ATF4 knockdown (HT or Atf4+/−) mice compared with wild-type mice (WT or Atf4+/+) mice. In conclusion, low serum IL-22 level is associated with SALI occurrence, and IL-22 pre-administration activates autophagy in hepatocytes and protects mice against LPS-induced ALI partially related to ATF4-ATG7 signaling pathway.

The Protective Effect of Aesculus hippocastanum (Venoplant®) Against Concanavalin A-Induced Liver Injury

Pharmacology ◽  
2019 ◽  
Vol 104 (3-4) ◽  
pp. 196-206 ◽  
Author(s):  
Shujin Wu ◽  
Rina Sa ◽  
Zhirong Gu ◽  
Pei Zhao ◽  
Jing Yu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Cytochrome C ◽  
Concanavalin A ◽  
Cell Apoptosis ◽  
Liver Tissue ◽  
Caspase 3 ◽  
Acute Liver Injury ◽  
Aesculus Hippocastanum ◽  
Tnf Α ◽  
Ifn Γ

Aim: The present study was performed to investigate the effect of Aesculus hippocastanum (AH; Venoplant®) on concanavalin A (ConA)-induced acute liver injury and explore the mechanism in mice. Methods: ConA (20 mg/kg) was administered via tail vein injection to induce hepatic damage. The groups of AH (Venoplant®) were given at 65.8, 131.6, and 263.2 mg/kg by oral gavages for 20 days. The serum levels of aspartate transaminase (AST), alanine aminotransferase (ALT), total protein (TP), and albumin (Alb) were determined by automatic biochemical analyzer, and the Alb/globulin (A/G) ratio was calculated. Tumor necrosis factor-α (TNF-α) and IFN-γ levels were assayed by enzyme-linked immunosorbent assay. The liver tissue was attained by hematoxylin and eosin, and the histopathological changes were calculated. The cell apoptosis was assayed by terminal dUTP nick-end labeling. The malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) content of liver tissue were assayed by related kits. The activity of caspase-3 was detected by spectrophotometry. The expressions of cytochrome c, Bax, Bcl-2, c-Jun N-terminal kinase (JNK), and p-JNK were detected by western blot. Results: The results showed that the levels of ALT, AST, IFN-γ, and TNF-α in AH (Venoplant®) groups were significantly lower than those in ConA-injured group, while the levels of TP, Alb, and A/G were significantly higher. The SOD and GSH levels were significantly increased, and the MDA level was decreased; liver histopathology was changed consistently with the serological indicators, AH (Venoplant®) treatment significantly reduced the pathological damage and cell apoptosis; while in AH (Venoplant®) group, the expressions of cytochrome c, caspase-3, Bax/Bcl-2 ratio, and p-JNK were significantly decreased. Conclusion: AH (Venoplant®) could significantly protect the ConA-induced acute liver injury in mice via inhibition of reactive oxygen species and JNK pathway.

scholarly journals SHED ameliorated concanavalin A-induced autoimmune hepatitis by protecting hepatocytes from apoptosis

2020 ◽  
Author(s):  
Yikun Zhou ◽  
Ruili Yang ◽  
Lingsu Zhu ◽  
Huaming Huang ◽  
Shengjie Cui ◽  
...  
Keyword(s):  
Liver Injury ◽  
Autoimmune Hepatitis ◽  
Concanavalin A ◽  
Acute Liver Injury ◽  
Deciduous Teeth ◽  
Protective Effects ◽  
Hepatocyte Apoptosis ◽  
Con A ◽  
Tnf Α ◽  
Ifn Γ

Abstract Background：Autoimmune hepatitis (AIH) is serious autoimmune liver diseases that threaten people’s health worldwide, emphasizing the need to identify novel treatment. Stem cells from human exfoliated deciduous teeth (SHED), which is easy to obtain and non-invasive, showed pronounced proliferation and immunomodulation capacity. This study aims to investigate the effect of SHED on ConA-induced AIH and the potential underlying mechanisms.Methods: We used a concanavalin A (ConA) induced acute hepatitis mouse model and in vitro co-culture system to study the protective effects of SHED on ConA-induced autoimmune hepatitis and the underlying mechanisms.Results: SHED infusion could prevent aberrant histopathological architecture of liver with infiltration of abundant of CD3+, CD4+, TNF-α+ and IFN-γ+ inflammatory cells induced by ConA. The expression of ALT and AST which indicated the liver function significantly elevated in hepatitis mice. While SHED infusion could block the elevation of ALT and AST induced by ConA. Mechanistically, Con-A upregulated TNF-α and IFN-γ expression activated NF-κB pathways to induced hepatocyte apoptosis, resulting in acute liver injury. SHED administration protected hepatocytes from Con-A-induced apoptosis. Conclusions: These results demonstrated that SHED alleviated ConA-induced acute liver injury via inhibition of hepatocyte apoptosis mediated by the NF-κB pathways. Our findings could provide a potential prevention and therapeutic strategy for hepatitis and acute hepatic injury.

IL-6, IFN-γ and TNF-α production by liver-associated T cells and acute liver injury in rats administered concanavalin A

1998 ◽  
Vol 76 (6) ◽  
pp. 542-549 ◽  
Author(s):  
Qi Cao ◽  
Robert Batey ◽  
Gerald Pang ◽  
Adrian Russell ◽  
Robert Clancy
Keyword(s):  
T Cells ◽  
Liver Injury ◽  
Concanavalin A ◽  
Acute Liver Injury ◽  
Tnf Α ◽  
Ifn Γ

scholarly journals Swift Development of Protective Effector Functions in Naive Cd8+ T Cells against Malaria Liver Stages

2001 ◽  
Vol 194 (2) ◽  
pp. 173-180 ◽  
Author(s):  
Gen-ichiro Sano ◽  
Julius C.R. Hafalla ◽  
Alexandre Morrot ◽  
Ryo Abe ◽  
Juan J. Lafaille ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
Cell Receptor ◽  
Plasmodium Yoelii ◽  
Parasite Development ◽  
Effector Functions ◽  
Ifn Γ

We generated T cell receptor transgenic mice specific for the liver stages of the rodent malaria parasite Plasmodium yoelii and studied the early events in the development of in vivo effector functions in antigen-specific CD8+ T cells. Differently to activated/memory cells, naive CD8+ T cells are not capable of exerting antiparasitic activity unless previously primed by parasite immunization. While naive cells need to differentiate before achieving effector status, the time required for this process is very short. Indeed, interferon (IFN)-γ and perforin mRNA are detectable 24 h after immunization and IFN-γ secretion and cytotoxic activity are detected ex vivo 24 and 48 h after immunization, respectively. In contrast, the proliferation of CD8+ T cells begins after 24 h and an increase in the total number of antigen-specific cells is detected only after 48 h. Remarkably, a strong CD8+ T cell–mediated inhibition of parasite development is observed in mice challenged with viable parasites only 24 h after immunization with attenuated parasites. These results indicate that differentiation of naive CD8+ T cells does not begin only after extensive cell division, rather this process precedes or occurs simultaneously with proliferation.

scholarly journals Single-cell RNA sequencing reveals ex vivo signatures of SARS-CoV-2-reactive T cells through ‘reverse phenotyping’

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
David S. Fischer ◽  
Meshal Ansari ◽  
Karolin I. Wagner ◽  
Sebastian Jarosch ◽  
Yiqi Huang ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Rna Sequencing ◽  
Ex Vivo ◽  
Severe Disease ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Single Cell Rna Sequencing

AbstractThe in vivo phenotypic profile of T cells reactive to severe acute respiratory syndrome (SARS)-CoV-2 antigens remains poorly understood. Conventional methods to detect antigen-reactive T cells require in vitro antigenic re-stimulation or highly individualized peptide-human leukocyte antigen (pHLA) multimers. Here, we use single-cell RNA sequencing to identify and profile SARS-CoV-2-reactive T cells from Coronavirus Disease 2019 (COVID-19) patients. To do so, we induce transcriptional shifts by antigenic stimulation in vitro and take advantage of natural T cell receptor (TCR) sequences of clonally expanded T cells as barcodes for ‘reverse phenotyping’. This allows identification of SARS-CoV-2-reactive TCRs and reveals phenotypic effects introduced by antigen-specific stimulation. We characterize transcriptional signatures of currently and previously activated SARS-CoV-2-reactive T cells, and show correspondence with phenotypes of T cells from the respiratory tract of patients with severe disease in the presence or absence of virus in independent cohorts. Reverse phenotyping is a powerful tool to provide an integrated insight into cellular states of SARS-CoV-2-reactive T cells across tissues and activation states.

scholarly journals Transcriptomic Analysis of Inbred Chicken Lines Reveals Infectious Bursal Disease Severity Is Associated with Greater Bursal Inflammation In Vivo and More Rapid Induction of Pro-Inflammatory Responses in Primary Bursal Cells Stimulated Ex Vivo

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 933
Author(s):  
Amin S. Asfor ◽  
Salik Nazki ◽  
Vishwanatha R.A.P. Reddy ◽  
Elle Campbell ◽  
Katherine L. Dulwich ◽  
...  
Keyword(s):  
Rho Gtpases ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Severe Disease ◽  
Infectious Bursal Disease ◽  
Rna Seq ◽  
Rapid Induction ◽  
Cytoskeletal Regulation ◽  
Bursal Disease

In order to better understand differences in the outcome of infectious bursal disease virus (IBDV) infection, we inoculated a very virulent (vv) strain into White Leghorn chickens of inbred line W that was previously reported to experience over 24% flock mortality, and three inbred lines (15I, C.B4 and 0) that were previously reported to display no mortality. Within each experimental group, some individuals experienced more severe disease than others but line 15I birds experienced milder disease based on average clinical scores, percentage of birds with gross pathology, average bursal lesion scores and average peak bursal virus titre. RNA-Seq analysis revealed that more severe disease in line W was associated with significant up-regulation of pathways involved in inflammation, cytoskeletal regulation by Rho GTPases, nicotinic acetylcholine receptor signaling, and Wnt signaling in the bursa compared to line 15I. Primary bursal cell populations isolated from uninfected line W birds contained a significantly greater percentage of KUL01+ macrophages than cells isolated from line 15I birds (p < 0.01) and, when stimulated ex vivo with LPS, showed more rapid up-regulation of pro-inflammatory gene expression than those from line 15I birds. We hypothesize that a more rapid induction of pro-inflammatory cytokine responses in bursal cells following IBDV infection leads to more severe disease in line W birds than in line 15I.

scholarly journals Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Koen Debackere ◽  
Lukas Marcelis ◽  
Sofie Demeyer ◽  
Marlies Vanden Bempt ◽  
Nicole Mentens ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Lymphoma ◽  
Ex Vivo ◽  
Cell Receptor ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Fusion Transcripts ◽  
Not Otherwise Specified

AbstractPeripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Up to 30% of PTCL lack distinctive features and are classified as PTCL, not otherwise specified (PTCL-NOS). To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we perform RNA-sequencing of 18 cases and validate results in an independent cohort of 37 PTCL cases. We identify FYN-TRAF3IP2, KHDRBS1-LCK and SIN3A-FOXO1 as new in-frame fusion transcripts, with FYN-TRAF3IP2 as a recurrent fusion detected in 8 of 55 cases. Using ex vivo and in vivo experiments, we demonstrate that FYN-TRAF3IP2 and KHDRBS1-LCK activate signaling pathways downstream of the T cell receptor (TCR) complex and confer therapeutic vulnerability to clinically available drugs.

scholarly journals 5-O-Demethylnobiletin Alleviates CCl4-Induced Acute Liver Injury by Equilibrating ROS-Mediated Apoptosis and Autophagy Induction

2021 ◽  
Vol 22 (3) ◽  
pp. 1083
Author(s):  
Sukkum Ngullie Chang ◽  
Se Ho Kim ◽  
Debasish Kumar Dey ◽  
Seon Min Park ◽  
Omaima Nasif ◽  
...  
Keyword(s):  
Liver Injury ◽  
Acute Liver Injury ◽  
Elevated Serum ◽  
In Vitro Study ◽  
Biological Properties ◽  
Autophagic Flux ◽  
Serum Aminotransferase ◽  
Ccl4 Treatment

Polymethoxyflavanoids (PMFs) have exhibited a vast array of therapeutic biological properties. 5-O-Demethylnobiletin (5-DN) is one such PMF having anti-inflammatory activity, yet its role in hepatoprotection has not been studied before. Results from in vitro study revealed that 5-DN did not exert a high level of cytotoxicity on HepG2 cells at 40 μM, and it was able to rescue HepG2 cell death induced by carbon tetrachloride (CCl4). Subsequently, we investigated acute liver injury on BALB/c mice induced by CCl4 through the intraperitoneal injection of 1 mL/kg CCl4 and co-administration of 5-DN at (1 and 2 mg/kg) by oral gavage for 15 days. The results illustrated that treatment with 5-DN attenuated CCl4-induced elevated serum aminotransferase (AST)/alanine aminotransferase (ALT) ratio and significantly ameliorated severe hepatic damage such as inflammation and fibrosis evidenced through lesser aberrations in the liver histology of 5-DN dose groups. Additionally, 5-DN efficiently counteracted and equilibrated the production of ROS accelerated by CCl4 and dramatically downregulated the expression of CYP2E1 vitally involved in converting CCl4 to toxic free radicals and also enhanced the antioxidant enzymes. 5-DN treatment also inhibited cell proliferation and inflammatory pathway abnormally regulated by CCl4 treatment. Furthermore, the apoptotic response induced by CCl4 treatment was remarkably reduced by enhanced Bcl-2 expression and noticeable reduction in Bax, Bid, cleaved caspase 3, caspase 9, and apaf-1 expression. 5-DN treatment also induced the conversion of LC3 and promoted the autophagic flux. Conclusively, 5-DN exhibited hepatoprotective effects in vitro and in vivo and prevented liver fibrosis induced by CCl4.

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