• Toxicological Research
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• v.31 no.1
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• pp.11-16
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• 2015

Our body's immune system has defense mechanisms against pathogens such as viruses and bacteria. Immune responses are primarily initiated by the activation of toll-like receptors (TLRs). In particular, TLR4 is well-characterized and is known to be activated by gram-negative bacteria and tissue damage signals. TLR4 requires myeloid differentiation factor 2 (MD2) as a co-receptor to recognize its ligand, lipopolysaccharides (LPS), which is an extracellular membrane component of gram-negative bacteria. Gambogic acid is a xanthonoid isolated from brownish or orange resin extracted from Garcinia hanburyi. Its primary effect is tumor suppression. Since inflammatory responses are related to the development of cancer, we hypothesized that gambogic acid may regulate TLR4 activation. Our results demonstrated that gambogic acid decreased the expression of pro-inflammatory cytokines ($TNF-{\alpha}$, IL-6, IL-12, and $IL-1{\beta}$) in both mRNA and protein levels in bone marrow-derived primary macrophages after stimulation with LPS. Gambogic acid did not inhibit the activation of Interferon regulatory factor 3 (IRF3) induced by TBK1 overexpression in a luciferase reporter gene assay using IFN-${\beta}$-PRD III-I-luc. An in vitro kinase assay using recombinant TBK1 revealed that gambogic acid did not directly inhibit TBK1 kinase activity, and instead suppressed the binding of LPS to MD2, as determined by an in vitro binding assay and confocal microscopy analysis. Together, our results demonstrate that gambogic acid disrupts LPS interaction with the TLR4/MD2 complex, the novel mechanism by which it suppresses TLR4 activation.

• BMB Reports
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• v.37 no.4
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• pp.507-514
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• 2004

Gamma irradiation ($\gamma$-IR) is reported to have diverse effects on immune cell apoptosis, survival and differentiation. In the present study, the immunomodulatory effect of a low dose $\gamma$-IR (5~10 Gy) was investigated, focusing on the role of NF-${\kappa}B$ in the induction of the B cell differentiation molecule, CD23/FceRII. In the human B cell line Ramos, $\gamma$-IR not only induced CD23 expression, but also augmented the IL-4-induced surface CD23 levels. While $\gamma$-IR did not cause STAT6 activation in these cells, it did induce both DNA binding and the transcriptional activity of NF-${\kappa}B$ in the $I{\kappa}B$ degradation-dependent manner. It was subsequently found that different NF-${\kappa}B$ regulating signals modulated the $\gamma$-IR-or IL-4-induced CD23 expression. Inhibitors of NF-${\kappa}B$ activation, such as PDTC and MG132, suppressed the $\gamma$-IR-mediated CD23 expression. In contrast, Ras, which potentiates $\gamma$-IR-induced NF-${\kappa}B$ activity in these cells, further augmented the $\gamma$-IR- or IL-4-induced CD23 levels, The induction of NF-${\kappa}B$ activation and the subsequent up-regulation of CD23 expression by $\gamma$-IR were also observed in monocytic cells. These results suggest that $\gamma$-IR, at specific dosages, can modulate immune cell differentiation through the activation of NF-${\kappa}B$, and this potentially affects the immune inflammatory response that is mediated by cytokines.

• Molecules and Cells
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• v.40 no.3
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• pp.163-168
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• 2017

Microglia are the primary resident immune cells of the central nervous system (CNS). They are the first line of defense of the brain's innate immune response against infection, injury, and diseases. Microglia respond to extracellular signals and engulf unwanted neuronal debris by phagocytosis, thereby maintaining normal cellular homeostasis in the CNS. Pathological stimuli such as neuronal injury induce transformation and activation of resting microglia with ramified morphology into a motile amoeboid form and activated microglia chemotax toward lesion site. This review outlines the current research on microglial activation and chemotaxis.

• Molecules and Cells
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• v.46 no.2
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• pp.120-129
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• 2023

Recent technical advances have enabled unbiased transcriptomic and epigenetic analysis of each cell, known as "single-cell analysis". Single-cell analysis has a variety of technical approaches to investigate the state of each cell, including mRNA levels (transcriptome), the immune repertoire (immune repertoire analysis), cell surface proteins (surface proteome analysis), chromatin accessibility (epigenome), and accordance with genome variants (eQTLs; expression quantitative trait loci). As an effective tool for investigating robust immune responses in coronavirus disease 2019 (COVID-19), many researchers performed single-cell analysis to capture the diverse, unbiased immune cell activation and differentiation. Despite challenges elucidating the complicated immune microenvironments of chronic inflammatory diseases using existing experimental methods, it is now possible to capture the simultaneous immune features of different cell types across inflamed tissues using various single-cell tools. In this review, we introduce patient-based and experimental mouse model research utilizing single-cell analyses in the field of chronic inflammatory diseases, as well as multi-organ atlas targeting immune cells.

• Journal of Life Science
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• v.33 no.5
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• pp.429-435
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• 2023

Epidemiological studies suggest that maternal infection, maternal stress, and environmental risk factors during pregnancy increase the risk of brain development abnormalities associated with cognitive impairment in the offspring and increase susceptibility to schizophrenia and autism spectrum disorder. Several animal models have demonstrated that maternal immune activation (MIA) is sufficient to induce abnormal brain development and behavioral defects in the fetus. When polyinosine:polycytodylic acid (poly I:C) or lipopolysaccharide (LPS), which is commonly used in maternal immune activation animal models, was introduced into a pregnant dam, an increase in pro-inflammatory cytokines and microglial activity was observed in the offspring's brain. Microglia are brain-resident immune cells that play a mediating role in the central nervous system, and they are responsible for various functions, such as phagocytosis, synapse formation and branching, and angiogenesis. Several studies have reported that microglia are activated in MIA offspring and influence offspring behavior through interactions with various cytokines. In addition, it has been reported that they play an important role in brain circuits through interactions with neurons and astrocytes. However, there is controversy concerning whether microglia are essential to brain development or lead to behavioral defects, and the exact mechanism remains unknown. Therefore, for the potential diagnosis and treatment of brain developmental disorders, a functional study of microglia should be conducted using MIA animal models.

• Molecular & Cellular Toxicology
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• v.5 no.1
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• pp.93-98
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• 2009

Stephania delavayi Diels. has been used as an immune activator or an anti-inflammatory drug in China. We examined the immune modulation effect and 7-days repeated-dose toxicity to validate its biological safety and efficiency. Mice were repeatedly administrated with 50 mg/kg S. delavayi Diels. daily by I.P for 7 days. S. delavayi Diels. induced B cell activation but had no effect on other immune cells such as T cell, natural killer (NK) cell, and macrophage ($M{\varphi}$). S. delavayi Diels.-treated group exhibited no statistical significance from the control group in physical conditions; body weight, complete blood count (CBC), serum biochemical indexes etc. There was no difference between the control group and S. delavayi Diels.-treated group in gross findings such as histopathological alteration. In conclusion, S. delavayi Diels. is safe above the dose of immune modulation.

• IMMUNE NETWORK
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• v.21 no.3
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• pp.18.1-18.13
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• 2021

TLR signaling is critical for broad scale immune recognition of pathogens and/or danger molecules. TLRs are particularly important for the activation and the maturation of cells comprising the innate immune response. In recent years it has become apparent that several different TLRs regulate the function of lymphocytes as well, albeit to a lesser degree compared to innate immunity. TLR2 heterodimerizes with either TLR1 or TLR6 to broadly recognize bacterial lipopeptides as well as several danger-associated molecular patterns. In general, TLR2 signaling promotes immune cell activation leading to tissue inflammation, which is advantageous for combating an infection. Conversely, inappropriate or dysfunctional TLR2 signaling leading to an overactive inflammatory response could be detrimental during sterile inflammation and autoimmune disease. This review will highlight and discuss recent research advances linking TLR2 engagement to autoimmune inflammation.

• Molecules and Cells
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• v.44 no.6
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• pp.408-421
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• 2021

The outbreak of coronavirus disease 2019 (COVID-19) has not only affected human health but also diverted the focus of research and derailed the world economy over the past year. Recently, vaccination against COVID-19 has begun, but further studies on effective therapeutic agents are still needed. The severity of COVID-19 is attributable to several factors such as the dysfunctional host immune response manifested by uncontrolled viral replication, type I interferon suppression, and release of impaired cytokines by the infected resident and recruited cells. Due to the evolving pathophysiology and direct involvement of the host immune system in COVID-19, the use of immune-modulating drugs is still challenging. For the use of immune-modulating drugs in severe COVID-19, it is important to balance the fight between the aggravated immune system and suppression of immune defense against the virus that causes secondary infection. In addition, the interplaying events that occur during virus-host interactions, such as activation of the host immune system, immune evasion mechanism of the virus, and manifestation of different stages of COVID-19, are disjunctive and require thorough streamlining. This review provides an update on the immunotherapeutic interventions implemented to combat COVID-19 along with the understanding of molecular aspects of the immune evasion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may provide opportunities to develop more effective and promising therapeutics.

• Clinical and Experimental Pediatrics
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• v.52 no.6
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• pp.649-654
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• 2009

The immune system is comprised of cells and molecules whose collective and coordinated response to the introduction of foreign substance is referred to as the immune response. Defense against microbes is mediated by the early reaction (innate immunity) and the late response (adaptive immunity). Innate immunity consists of the epithelial barrier, phagocytes, complement and natural killer cells. Adaptive immunity, a more complex defense reaction, consists of activation of later-developed lymphocytes that, when stimulated by exposure to infectious agents, increase in magnitude and defensive capabilities with each successive exposure. In this review we discuss recent advances in important primary immune deficiency disorders of innate immunity (chronic granulomatous disease, leukocyte adhesion deficiency) and adaptive immunity (severe combined immune deficiency, Wiskott- Aldrich syndrome).

• IMMUNE NETWORK
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• v.12 no.3
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• pp.71-83
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• 2012

T cell activation and function require physical contact with antigen presenting cells at a specialized junctional structure known as the immunological synapse. Once formed, the immunological synapse leads to sustained T cell receptor-mediated signalling and stabilized adhesion. High resolution microscopy indeed had a great impact in understanding the function and dynamic structure of immunological synapse. Trends of recent research are now moving towards understanding the mechanical part of immune system, expanding our knowledge in mechanosensitivity, force generation, and biophysics of cell-cell interaction. Actin cytoskeleton plays inevitable role in adaptive immune system, allowing it to bear dynamic and precise characteristics at the same time. The regulation of mechanical engine seems very complicated and overlapping, but it enables cells to be very sensitive to external signals such as surface rigidity. In this review, we focus on actin regulators and how immune cells regulate dynamic actin rearrangement process to drive the formation of immunological synapse.