scholarly journals Fc Receptor Variants and Disease: A Crucial Factor to Consider in the Antibody Therapeutics in Clinic

2021 ◽  
Vol 22 (17) ◽  
pp. 9489
Author(s):  
Jin Kim ◽  
Ji Young Lee ◽  
Han Gil Kim ◽  
Min Woo Kwak ◽  
Tae Hyun Kang
Keyword(s):  
Signal Transduction ◽  
Endothelial Cells ◽  
Individual Differences ◽  
Genetic Variants ◽  
Promoter Region ◽  
Control Point ◽  
Protective Function ◽  
Effector Functions ◽  
Antibody Therapeutics ◽  
Antibody Function

The fragment crystallizable (Fc) domain of antibodies is responsible for their protective function and long-lasting serum half-life via Fc-mediated effector function, transcytosis, and recycling through its interaction with Fc receptors (FcRs) expressed on various immune leukocytes, epithelial, and endothelial cells. Therefore, the Fc–FcRs interaction is a control point of both endogenous and therapeutic antibody function. There are a number of reported genetic variants of FcRs, which include polymorphisms in (i) extracellular domain of FcRs, which change their affinities to Fc domain of antibodies; (ii) both cytoplasmic and intracellular domain, which alters the extent of signal transduction; and (iii) the promoter region of the FcRs gene, which affects the expression level of FcRs, thus being associated with the pathogenesis of disease indications. In this review, we firstly describe the correlation between the genetic variants of FcRs and immunological disorders by individual differences in the extent of FcRs-mediated regulations. Secondly, we discuss the influence of the genetic variants of FcRs on the susceptibility to infectious diseases or cancer in the perspective of FcRs-induced effector functions. Overall, we concluded that the genetic variants of FcRs are one of the key elements in the design of antibody therapeutics due to their variety of clinical outcomes among individuals.

Signal Transduction of Vascular Endothelial Cells

1995 ◽  
Vol 6 (2) ◽  
pp. 67-73
Author(s):  
Michihiko KUWANO ◽  
Hiroto IZUMI ◽  
Tadahisa SHONO ◽  
Sei-ichiro JIMI ◽  
Yukihiro WAKABAYASHI ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial

scholarly journals Melatonin and Microglia

2021 ◽  
Vol 22 (15) ◽  
pp. 8296
Author(s):  
Rüdiger Hardeland
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Signal Transduction ◽  
Endothelial Cells ◽  
Bacterial Infections ◽  
Melatonin Receptors ◽  
Sterile Inflammation ◽  
High Complexity ◽  
Anti Inflammatory ◽  
Multiple Signaling

Melatonin interacts in multiple ways with microglia, both directly and, via routes of crosstalk with astrocytes and neurons, indirectly. These effects of melatonin are of relevance in terms of antioxidative protection, not only concerning free-radical detoxification, but also in prevention of processes that cause, promote, or propagate oxidative stress and neurodegeneration, such as overexcitation, toxicological insults, viral and bacterial infections, and sterile inflammation of different grades. The immunological interplay in the CNS, with microglia playing a central role, is of high complexity and includes signaling toward endothelial cells and other leukocytes by cytokines, chemokines, nitric oxide, and eikosanoids. Melatonin interferes with these processes in multiple signaling routes and steps. In addition to canonical signal transduction by MT1 and MT2 melatonin receptors, secondary and tertiary signaling is of relevance and has to be considered, e.g., via the upregulation of sirtuins and the modulation of pro- and anti-inflammatory microRNAs. Many details concerning the modulation of macrophage functionality by melatonin are obviously also applicable to microglial cells. Of particular interest is the polarization toward M2 subtypes instead of M1, i.e., in favor of being anti-inflammatory at the expense of proinflammatory activities, which is well-documented in macrophages but also applies to microglia.

The association between selected genetic variants and individual differences in experimental pain

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Marie Udnesseter Lie ◽  
Bendik Winsvold ◽  
Johannes Gjerstad ◽  
Dagfinn Matre ◽  
Linda M. Pedersen ◽  
...  
Keyword(s):  
Individual Differences ◽  
Genetic Variants ◽  
Pain Threshold ◽  
Experimental Pain ◽  
Pain Tolerance ◽  
Heat Pain ◽  
Low Back ◽  
Secondary Hyperalgesia ◽  
Heat Pain Threshold ◽  
Pain Patients

AbstractObjectivesThe underlying mechanisms for individual differences in experimental pain are not fully understood, but genetic susceptibility is hypothesized to explain some of these differences. In the present study we focus on three genetic variants important for modulating experimental pain related to serotonin (SLC6A4 5-HTTLPR/rs25531 A>G), catecholamine (COMT rs4680 Val158Met) and opioid (OPRM1 rs1799971 A118G) signaling. We aimed to investigate associations between each of the selected genetic variants and individual differences in experimental pain.MethodsIn total 356 subjects (232 low back pain patients and 124 healthy volunteers) were genotyped and assessed with tests of heat pain threshold, pressure pain thresholds, heat pain tolerance, conditioned pain modulation (CPM), offset analgesia, temporal summation and secondary hyperalgesia. Low back pain patients and healthy volunteers did not differ in regards to experimental test results or allelic frequencies, and were therefore analyzed as one group. The associations were tested using analysis of variance and the Kruskal-Wallis test.ResultsNo significant associations were observed between the genetic variants (SLC6A4 5-HTTLPR/rs25531 A>G, COMT rs4680 Val158Met and OPRM1 rs1799971 A118G) and individual differences in experimental pain (heat pain threshold, pressure pain threshold, heat pain tolerance, CPM, offset analgesia, temporal summation and secondary hyperalgesia).ConclusionsThe selected pain-associated genetic variants were not associated with individual differences in experimental pain. Genetic variants well known for playing central roles in pain perception failed to explain individual differences in experimental pain in 356 subjects. The finding is an important contribution to the literature, which often consists of studies with lower sample size and one or few experimental pain assessments.

Heterogeneity of the signal transduction pathways for VEGF-induced MAPKs activation in human vascular endothelial cells

2001 ◽  
Vol 188 (2) ◽  
pp. 201-210 ◽  
Author(s):  
Rei Yashima ◽  
Mayumi Abe ◽  
Katsuhiro Tanaka ◽  
Hikaru Ueno ◽  
Kenya Shitara ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Signal Transduction Pathways ◽  
Vascular Endothelial

The interplay of genotype and environment in the development of fear and anxiety

e-Neuroforum ◽  
2013 ◽  
Vol 19 (3) ◽  
Author(s):  
N. Sachser ◽  
K.-P. Lesch
Keyword(s):  
Individual Differences ◽  
Environmental Factors ◽  
Anxiety Disorders ◽  
Candidate Gene ◽  
Early Development ◽  
Genetic Variants ◽  
External Influences ◽  
Postnatal Environment ◽  
Fear And Anxiety

AbstractIndividual differences in fear, anxiety, and the etiology of anxiety disorders develop dur­ing ontogeny. They are due to both genet­ic and environmental factors. With regard to the role of the environment, the organism is most susceptible to external influences dur­ing early development. Accordingly, stressors that impinge on the maternal organism dur­ing pregnancy evoke high levels of anxiety in the offspring later in life, as does an adverse early postnatal environment. However, anxi­ety-related circuits in the central nervous sys­tem retain their plasticity in adulthood, i.e., levels of anxiety can also be modified by ex­perience across the entire successive lifespan. Notably, the effects of external stressors on the individual’s level of anxiety are modulat­ed by genotype. Such genotype-by-environ­ment interactions are particularly well stud­ied in relation to genetic variants that modu­late the function of the serotonin transport­er. Thus, this review focuses on this candidate gene to elucidate the interplay of genotype and environment in the development of fear and anxiety.

scholarly journals Endothelial Cells Require STAT3 for Protection against Endotoxin-induced Inf lammation

2003 ◽  
Vol 198 (10) ◽  
pp. 1517-1525 ◽  
Author(s):  
Arihiro Kano ◽  
Michael J. Wolfgang ◽  
Qian Gao ◽  
Joerg Jacoby ◽  
Gui-Xuan Chai ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transforming Growth Factor ◽  
Endotoxic Shock ◽  
Transforming Growth Factor Β ◽  
Organ Damage ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Protective Function ◽  
Lps Challenge

Endothelial cells (ECs) are believed to be an important component in the protection from lipopolysaccharide (LPS)-induced endotoxic shock. However, the cellular and molecular mechanism is not well defined. Here, we report that signal transducer and activator of transcription (STAT) 3 is an essential regulator of the antiinflammatory function of ECs in systemic immunity. Because STAT3 deficiency results in early embryonic lethality, we have generated mice with a conditional STAT3 deletion in endothelium (STAT3E−/−). STAT3E−/− mice are healthy and fertile, and isolated ECs initiate normal tube formation in vitro. Conditional endothelial but not organ-specific (i.e., hepatocyte or cardiomyocyte) STAT3 knockout mice show an increased susceptibility to lethality after LPS challenge. The LPS response in STAT3E−/− mice shows exaggerated inflammation and leukocyte infiltration in multiple organs combined with elevated activity of serum alanine aminotransferase and aspartate aminotransferase, indicating organ damage. Concomitantly, proinflammatory cytokines are produced at an exaggerated level and for a prolonged period. This defect cannot be explained by lack of antiinflammatory cytokines, such as interleukin 10 and transforming growth factor β. Instead, we have shown that a soluble activity derived from endothelia and dependent on STAT3 is critical for suppression of interferon γ. These data define STAT3 signaling within endothelia as a critical antiinflammatory mediator and provide new insight to the protective function of ECs in inflammation.

scholarly journals Study on the Mechanism of Capillary Leakage Caused by Hypoxia-Inducible Factor-1α through Inducing High Expression of Matrix Metalloproteinase-9

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Huili Li ◽  
He Huang ◽  
Yunliang Cui ◽  
Weiwei Li ◽  
Shuliu Zhang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Matrix Metalloproteinase ◽  
Promoter Region ◽  
Hypoxia Inducible Factor ◽  
High Expression ◽  
Capillary Leakage ◽  
Sirna Transfection ◽  
Hypoxia Response ◽  
Hypoxia Inducible Factor 1Α ◽  
Metalloproteinase 9

Purposes. This study mainly explored the mechanism of capillary leakage caused by hypoxia-inducible factor-1α through inducing high expression of matrix metalloproteinase-9. Method. We established a monolayer endothelial cell model by culturing human umbilical vein endothelial cells (HUVEC) in vitro, used tumor necrosis factor (TNFα) and HIF-1α inhibitor 2-methoxyestradiol (2ME2) to act on HUVEC, and at the same time constructed siRNA-transfected HUVEC to interfere with the expression of HIF-1α. The permeability of monolayer endothelial cells was measured by transwell chamber method, the concentration of MMP-9 in the supernatant was measured by ELISA method, the expression of key molecules related to permeability (HIF- 1α, MMP-9, claudin-5, and ZO-1) was measured by RT-PCR and Western blot method, and the localization and expression of claudin-5 and ZO-1 were measured by immunofluorescence method. We searched for 7 HIF-1α hypoxia response elements within 4000 bp before the transcription start site in the MMP-9 promoter region, constructed the MMP-9 promoter-luciferase reporter gene recombinant plasmid, transfected and stimulated HUVEC with TNFα, and detected the effect of 7 hypoxia response element plasmids on the transcription activity of MMP-9 promoter. Results. Under the action of TNFα, the permeability of monolayer endothelial cells increased, and the concentration of MMP-9 in the cell supernatant increased. 2ME2 and HIF-1α-siRNA transfection can improve the above situation ( P < 0.05 ). 2ME2 and HIF-1α-siRNA transfection can inhibit the high expression of HIF-1α and MMP-9 caused by TNFα, thereby increasing the expression of claudin-5 and ZO-1 ( P < 0.05 ). 2ME2 and HIF-1α-siRNA transfection can reduce the inhibition of TNFα on the expression of cell membrane protein claudin-5 and tight junction protein ZO-1. Element 1, element 5, and element 7 are the sites where HIF-1α interacts with MMP-9 at the transcription level. Conclusion. This study shows that HIF-1α can increase the permeability of monolayer epithelial cells by inducing the high expression of MMP-9, leading to capillary leakage. Its target is at the −3798 bp, −1878 bp, and −1489 bp points of the transcription initiation site in the MMP-9 promoter region.

scholarly journals TNF-α Activates High-Mobility Group Box 1 - Toll-Like Receptor 4 Signaling Pathway in Human Aortic Endothelial Cells

2016 ◽  
Vol 38 (6) ◽  
pp. 2139-2151 ◽  
Author(s):  
Won Seok Yang ◽  
Nam Jeong Han ◽  
Jin Ju Kim ◽  
Mee Jeong Lee ◽  
Su-Kil Park
Keyword(s):  
Signal Transduction ◽  
Endothelial Cells ◽  
High Mobility ◽  
Neutralizing Antibody ◽  
High Mobility Group ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Aortic Endothelial Cells ◽  
Tnf Α ◽  
Human Aortic Endothelial Cells

Background/Aims: Toll-like receptor 4 (TLR4) interacts with endogenous substances as well as lipopolysaccharide. We explored whether TLR4 is implicated in tumor necrosis factor-α (TNF-α) signal transduction in human aortic endothelial cells. Methods: The pathway was evaluated by transfection of siRNAs, immunoprecipitation and Western blot analysis. Results: TNF-α activated spleen tyrosine kinase (Syk) within 10 min, which led to endothelin-1 (ET-1) production. TLR4 was also rapidly activated by TNF-α stimulation, as shown by recruitment of interleukin-1 receptor-associated kinase 1 to TLR4 and its adaptor molecule, myeloid differentiation factor 88 (MyD88). siRNA depletion of TLR4 markedly attenuated TNF-α-induced Syk activation and ET-1 production. TLR4 inhibitor (CLI-095), TLR4-neutralizing antibody and siRNA depletion of MyD88 also attenuated TNF-α-induced Syk activation. Syk was co-immunoprecipitated with TLR4, and TNF-α activated Syk bound to TLR4. High-mobility group box 1 (HMGB1) was rapidly released and associated with TLR4 after TNF-α stimulation with a peak at 5 min, which was prevented by N-acetylcysteine, an antioxidant. Glycyrrhizin (HMGB1 inhibitor), HMGB1-neutralizing antibody and siRNA depletion of HMGB1 all suppressed TNF-α-induced Syk activation and ET-1 production. Conclusion: Upon TNF-α stimulation, TLR4 is activated by HMGB1 that is immediately released after the generation of reactive oxygen species, and plays a crucial role in the signal transduction.

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