Abstract:
:Liver injury after experimental acetaminophen treatment is mediated both by direct hepatocyte injury through a P450-generated toxic metabolite and indirectly by activated liver Kupffer cells and neutrophils. This study was designed to investigate the role of Notch signaling in the regulation of innate immune responses in acetaminophen (APAP)-induced liver injury. Using a mouse model of APAP-induced liver injury, wild-type (WT) and toll-like receptor 4 knockout (TLR4 KO) mice were injected intraperitoneally with APAP or PBS. Some animals were injected with γ-secretase inhibitor DAPT or DMSO vehicle. For the in vitro study, bone marrow-derived macrophages (BMMs) were transfected with Notch1 siRNA, TLR4 siRNA, and non-specific (NS) siRNA and stimulated with LPS. Indeed, paracetamol/acetaminophen-induced liver damage was worse after Notch blockade with DAPT in wild-type mice, which was accompanied by significantly increased ALT levels, diminished hairy and enhancer of split-1 (Hes1), and phosphorylated Stat3 and Akt but enhanced high mobility group box 1 (HMGB1), TLR4, NF-κB, and NLRP3 activation after APAP challenge. Mice receiving DAPT increased macrophage and neutrophil accumulation and hepatocellular apoptosis. However, TLR4 KO mice that received DAPT reduced APAP-induced liver damage and NF-κB, NLRP3, and cleaved caspase-1 activation. BMMs transfected with Notch1 siRNA reduced Hes1 and phosphorylated Stat3 and Akt but augmented HMGB1, TLR4, NF-κB, and NLRP3. Furthermore, TLR4 siRNA knockdown resulted in decreased NF-κB and NLRP3 and cleaved caspase-1 and IL-1β levels following LPS stimulation. These results demonstrate that Notch signaling regulates innate NLRP3 inflammasome activation through regulation of HMGB1/TLR4/NF-κB activation in APAP-induced liver injury. Our novel findings underscore the critical role of the Notch1-Hes1 signaling cascade in the regulation of innate immunity in APAP-triggered liver inflammation. This might imply a novel therapeutic potential for the drug-induced damage-associated lethal hepatitis.
journal_name
Immunol Resjournal_title
Immunologic researchauthors
Jiang L,Ke M,Yue S,Xiao W,Yan Y,Deng X,Ying QL,Li J,Ke Bdoi
10.1007/s12026-017-8913-3subject
Has Abstractpub_date
2017-06-01 00:00:00pages
739-749issue
3eissn
0257-277Xissn
1559-0755pii
10.1007/s12026-017-8913-3journal_volume
65pub_type
杂志文章abstract::This is a journey that began in medical school at Stanford in 1963 and that is still underway, now as faculty member here for the past 40 years. History is by its nature selective, and I chose highlights that reflect on the remarkable progress we have made using the immune system to treat cancer. We will never be sati...
journal_title:Immunologic research
pub_type: 传,历史文章,杂志文章,评审
doi:10.1007/s12026-014-8506-3
更新日期:2014-05-01 00:00:00
abstract::Interleukin (IL)-21 is a member of the γ chain-receptor cytokine family along with IL-2, IL-4, IL-7, IL-9, and IL-15. The effects of IL-21 are pleiotropic, owing to the broad cellular distribution of the IL-21 receptor. IL-21 is secreted by activated CD4 T cells and natural killer T cells. Within CD4 T cells, its secr...
journal_title:Immunologic research
pub_type: 杂志文章,评审
doi:10.1007/s12026-013-8457-0
更新日期:2013-12-01 00:00:00
abstract::Dendritic cells (DCs) are known to play an important role in initiating and orchestrating antimicrobial immunity. Given the fact that candidiasis appears often in immunocompromised patients, it seems plausible that DCs hold the key to new antifungal strategies. One possibility to enhance the potency of DC-based immuno...
journal_title:Immunologic research
pub_type: 杂志文章
doi:10.1007/s12026-014-8562-8
更新日期:2015-03-01 00:00:00
abstract::Aberrant T helper-2 (Th2) responses play a critical role in the pathogenesis of allergic diseases. The underlying mechanism is to be further investigated. It is reported that soluble CD83 (sCD83) has immune-regulatory effects. This study aims to investigate the role of sCD83 in the regulation of Th2 polarization. Bloo...
journal_title:Immunologic research
pub_type: 杂志文章
doi:10.1007/s12026-020-09133-9
更新日期:2020-06-01 00:00:00
abstract::The Caenorhabditis elegans model can be used to study Candida albicans virulence and host immunity, as well as to identify plant-derived natural products to use against C. albicans. Thymol is a hydrophobic phenol compound from the aromatic plant thyme. In this study, the in vitro data demonstrated concentration-depend...
journal_title:Immunologic research
pub_type: 杂志文章
doi:10.1007/s12026-016-8785-y
更新日期:2016-08-01 00:00:00
abstract::The proteins of the tumor necrosis factor (TNF) receptor superfamily are a group of cell-surface receptors critically involved in the maintenance of homeostasis of the immune system. By interacting with their corresponding ligands, these receptors either induce cell death or promote cell survival of immune cells. The ...
journal_title:Immunologic research
pub_type: 杂志文章,评审
doi:10.1385/IR:26:1-3:323
更新日期:2002-01-01 00:00:00
abstract::Monoclonal antibodies (mAb) have been used as targeted treatments against cancer for more than a decade, with mixed results. Research is needed to understand mAb mechanisms of action with the goal of improving the efficacy of currently used mAbs and guiding the design of novel mAbs. While some mAb-induced tumor cell k...
journal_title:Immunologic research
pub_type: 杂志文章,评审
doi:10.1007/s12026-014-8542-z
更新日期:2014-08-01 00:00:00
abstract::IgA nephropathy (IgAN) is an autoimmune disease associated with complement activation. It is unclear whether the ratio of serum C3 and C4 concentrations (C3/C4 ratio) can predict renal outcomes in IgAN patients. A total of 1503 patients diagnosed with IgAN via renal biopsy were recorded in this study. Poor renal outco...
journal_title:Immunologic research
pub_type: 杂志文章
doi:10.1007/s12026-018-8995-6
更新日期:2018-06-01 00:00:00
abstract::Allogeneic hematopoietic stem cell transplantation (HSCT) currently provides the only chance of curative therapy for many patients with hematological malignancies. Owing to the excess morbidity and mortality observed in less robust patients, this approach has traditionally been limited to younger patients without sign...
journal_title:Immunologic research
pub_type: 杂志文章,评审
doi:10.1385/IR:28:1:1
更新日期:2003-01-01 00:00:00
abstract::Type I diabetes (T1D) is a chronic autoimmune disease caused by pancreatic β-cell destruction induced by autoantibodies and autoreactive T cells. After significant reduction of the β-cell mass, diabetes sets in and can cause significant complications. It is estimated that more than 3 million Americans have T1D, and it...
journal_title:Immunologic research
pub_type: 杂志文章,评审
doi:10.1007/s12026-014-8546-8
更新日期:2014-08-01 00:00:00
abstract::The "X chromosome-nucleolus nexus" hypothesis provides a comprehensive explanation of how autoantibodies can develop following cellular stress. The hypothesis connects autoimmune diseases with the impact of environmental factors, such as viruses, through epigenetic disruption. The inactive X chromosome, a major epigen...
journal_title:Immunologic research
pub_type: 杂志文章,评审
doi:10.1007/s12026-018-9044-1
更新日期:2018-12-01 00:00:00
abstract::Our laboratory has studied the role of CD40 ligand (CD40L, CD154) in the primate immune response to allogenic and infectious challenges. We find that intensive early blockade of CD40L reliably attenuates acute rejection of primate cardiac allografts. Monotherapy fails to prevent late graft loss, which often occurs in ...
journal_title:Immunologic research
pub_type: 杂志文章
doi:10.1385/IR:23:2-3:253
更新日期:2001-01-01 00:00:00
abstract::There is increasing documentation of significant survival benefits achieved in cancer patients treated with hyperthermia in combination with radiation and/or chemotherapy. Most evidence collected regarding the mechanisms by which hyperthermia positively influences tumor control has centered on in vitro data showing th...
journal_title:Immunologic research
pub_type: 杂志文章,评审
doi:10.1007/s12026-009-8115-8
更新日期:2010-03-01 00:00:00
abstract::Contrasting results have been reported about the prevalence of thyroid autoimmunity (AT) and dysfunction (TD) in patients with psoriatic arthritis (PsA). In this study, we pointed to evaluate the incidence of new cases of clinical and subclinical TD in a broad group of patients with PsA versus a control group, matched...
journal_title:Immunologic research
pub_type: 杂志文章
doi:10.1007/s12026-017-8900-8
更新日期:2017-06-01 00:00:00
abstract::For the last decade, we have focused on guanylyl cyclase C (GUCY2C) as a potentially ideal target antigen for colorectal cancer immunotherapy. GUCY2C is expressed only in intestinal epithelial cells and by nearly 100% of colorectal cancers. We have developed and tested a recombinant adenoviral vector possessing GUCY2C...
journal_title:Immunologic research
pub_type: 杂志文章,评审
doi:10.1007/s12026-011-8253-7
更新日期:2011-12-01 00:00:00
abstract::Type 1 diabetes (T1D) is a chronic autoimmune disease in which β cells are destroyed. Islet transplantation is the most promising therapeutic treatment for T1D patients. However, allograft rejection and autoimmune reaction have been recognized as primary causes of graft loss after transplantation. Alpha-1-antitrypsin ...
journal_title:Immunologic research
pub_type: 杂志文章
doi:10.1007/s12026-015-8636-2
更新日期:2015-05-01 00:00:00
abstract::Recent studies have elucidated unanticipated connections between the immune and skeletal systems, and this relationship has led to the development of a new field known as osteoimmunology. The goal of research in this field is to: (1) further understand how the bone microenvironment influences immune cell ontogeny and ...
journal_title:Immunologic research
pub_type: 杂志文章,评审
doi:10.1007/s12026-009-8093-x
更新日期:2009-12-01 00:00:00
abstract::Current approaches for hematopoietic stem cell (HSC) and organ transplantation are limited by donor and host-mediated immune responses to allo-antigens. Application of these therapies is limited by the toxicity of preparative and post-transplant immunosuppressive regimens and a shortage of appropriate HLA-matched dono...
journal_title:Immunologic research
pub_type: 杂志文章
doi:10.1007/s12026-008-8088-z
更新日期:2009-01-01 00:00:00
abstract::Anti-rods and rings (anti-RR) antibody induction is related to the combination of interferon and ribavirin in the treatment of hepatitis C virus (HCV) infection. If the main factor leading to this autoimmune reaction is the combination of these drugs, is not well known, but in vitro studies shows that ribavirin alone ...
journal_title:Immunologic research
pub_type: 杂志文章
doi:10.1007/s12026-020-09136-6
更新日期:2020-06-01 00:00:00
abstract::This review of the events leading to the New Era of Immunology focuses on the important leads provided by the Experiments of Nature. Not only did they provide the path that led to our present knowledge of the ontogeny of the immune system, but also to an entirely new perspective of lymphocytic malignancies. The power ...
journal_title:Immunologic research
pub_type: 历史文章,杂志文章
doi:10.1007/s12026-007-0047-6
更新日期:2007-01-01 00:00:00
abstract::Considerable progress has been made in understanding the Fas pathway at the molecular and cellular levels, but fundamental questions about the overall biological role of the Fas pathway remain unresolved. A major question is why lymphoproliferation caused by the lpr mutation of Fas and gld mutation of FasL ligand (Fas...
journal_title:Immunologic research
pub_type: 杂志文章,评审
doi:10.1007/s12026-009-8144-3
更新日期:2010-07-01 00:00:00
abstract::Neutrophils are key effector cells of the innate immune system and are involved in the host defense against invading pathogens such as viruses. Recently, it was reported that HIV-1-neutrophil interaction triggers neutrophil activation and promotes expression of Toll-like receptors (TLRs). Here, we assessed the role of...
journal_title:Immunologic research
pub_type: 杂志文章
doi:10.1007/s12026-016-8876-9
更新日期:2016-12-01 00:00:00
abstract::Research during the last decade has significantly advanced our understanding of the molecular mechanisms at the interface between the nervous system and the immune system. Insight into bidirectional neuro-immune communication has characterized the nervous system as an important partner of the immune system in the regu...
journal_title:Immunologic research
pub_type: 杂志文章,评审
doi:10.1007/s12026-015-8718-1
更新日期:2015-12-01 00:00:00
abstract::The intestinal epithelium serves as one of human's primary interfaces with the outside world. This interface is very heavily colonized with bacteria and yet permits absorption of life-sustaining nutrients while protecting the tissues below from microbial onslaught. Although the gut epithelium had been classically thou...
journal_title:Immunologic research
pub_type: 杂志文章,评审
doi:10.1385/IR:29:1-3:055
更新日期:2004-01-01 00:00:00
abstract::In the murine splenocytes, CD8α+ dendritic cells (abbreviated as 8+DC) and CD8α- dendritic cells (abbreviated as 8-DC) are identified with some vague features for each of them. 8+DCs but not 8-DCs cross-prime cytotoxic T cells in vivo. We aim to distinguish the two subtypes of DC based on gene expression profiling. Su...
journal_title:Immunologic research
pub_type: 杂志文章
doi:10.1007/s12026-011-8237-7
更新日期:2011-10-01 00:00:00
abstract::Increased numbers of CD8+CD28neg. T cells have been detected in the peripheral blood of patients with several types of malignancies. However, the role of these cells in anticancer immunity are not yet clear and CD8+CD28neg. T cells are a controversially discussed subpopulation reported both as immunosuppressive and cy...
journal_title:Immunologic research
pub_type: 杂志文章
doi:10.1007/s12026-017-8976-1
更新日期:2018-02-01 00:00:00
abstract::The distinction that in areas where helminthic infections are common, autoimmune diseases are less prevalent, led to the investigation of immune modulatory properties of helminths and their derivatives. Such are phosphorylcholine (PC) moieties which are a component of secreted products of helminths. PC has been broadl...
journal_title:Immunologic research
pub_type: 杂志文章,评审
doi:10.1007/s12026-018-9051-2
更新日期:2018-12-01 00:00:00
abstract::The tick-borne encephalitis (TBE) serocomplex of viruses, genus Flavivirus, includes a number of important human pathogens that cause serious neurological illnesses and hemorrhagic fevers. These viruses pose a significant public health problem due to high rates of morbidity and mortality, their emergence to new geogra...
journal_title:Immunologic research
pub_type: 杂志文章
doi:10.1007/s12026-008-8065-6
更新日期:2009-01-01 00:00:00
abstract::The two-signal model of T cell activation states that antigen recognition by TCR provides a tolerogenic signal (termed Signal 1) unless the T cell receives simultaneous costimulation (Signal 2) that permits antigen recognition to prime activation. Our efforts to characterize genetic and biochemical factors resulting f...
journal_title:Immunologic research
pub_type: 杂志文章,评审
doi:10.1007/s12026-009-8147-0
更新日期:2010-07-01 00:00:00
abstract::Mutations of the Wiskott-Aldrich Syndrome Protein (WASP) are responsible for classic Wiskott-Aldrich Syndrome (WAS), X-linked thrombocytopenia (XLT), and in rare instances congenital X-linked neutropenia (XLN). WASP is a regulator of actin polymerization in hematopoietic cells with well-defined functional domains that...
journal_title:Immunologic research
pub_type: 杂志文章,评审
doi:10.1007/s12026-008-8084-3
更新日期:2009-01-01 00:00:00