Stable expression ratios of five pyroptosis-inducing cytokines in the spleen and thymus of mice showed potential immune regulation at the organ level

Lupus ◽  
2020 ◽  
Vol 29 (3) ◽  
pp. 290-302
Author(s):  
H Fan ◽  
S Zhang ◽  
N Li ◽  
P Fan ◽  
X Hu ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune System ◽  
Inflammatory Cytokines ◽  
Lupus Erythematosus ◽  
Immune Regulation ◽  
Interleukin 18 ◽  
Systemic Lupus ◽  
Tnf Α ◽  
Organ Level ◽  
Pro Inflammatory Cytokines

Background The immune system is one of the most complex regulatory systems in the body and is essential for the maintenance of homeostasis. Despite recent breakthroughs in immunology, the regulation of the immune system and the etiology of autoimmune diseases such as lupus remain unclear. Systemic lupus erythematosus is a systemic autoimmune disease with abnormally and inconsistently expressed pro-inflammatory cytokines. Pyroptosis is a pro-inflammatory form of programmed cell death that is associated with systemic lupus erythematosus. The thymus and spleen are important immune organs involved in systemic lupus erythematosus. Therefore, this study investigated the difference in expression of pyroptosis-inducing pro-inflammatory cytokines between the spleen and thymus in lupus model mice and in control mice, to describe immune regulation at the organ level. Objective To investigate differences in the expression of pyroptosis-inducing cytokines in the spleen and thymus and to explore immune regulatory networks at the organ level. Methods Two groups of lupus mice and two groups of control mice were utilized for this study. Using the thymus and spleen of experimental animals, mRNA expression levels of five pyroptosis-inducing cytokines (interleukin 1β, interleukin 18, NLRP3, caspase-1 and TNF-α) were determined via quantitative polymerase chain reaction. In addition, tissue distribution of these cytokines was investigated via immunohistochemistry. Results All five pyroptosis-inducing inflammatory cytokines showed higher expression in the spleen than in the thymus ( p < 0.05). Moreover, the spleen/thymus expression ratios of all five pyroptosis-inducing cytokines were not statistically different between the four experimental groups. Expression of all five cytokines exhibited a stable ratio (spleen/thymus ratios). This distinctive stable spleen/thymus ratio was consistent in all four experimental groups. The stable spleen/thymus ratios of the five inflammatory cytokines were as follows: interleukin 1β (2.02 ± 0.9), interleukin 18 (2.07 ± 1.06), caspase-1 (1.93 ± 0.66), NLRP3 (3.14 ± 1.61) and TNF-α (3.16 ± 1.36). Immunohistochemical analysis showed the cytokines were mainly expressed in the red pulp region of the spleen and the medullary region of the thymus, where immune-activated cells aggregated. Conclusion The stable spleen/thymus expression ratios of pyroptosis-inducing cytokines indicated that immune organs exhibit strictly regulated functions to maintain immune homeostasis and adapt to the environment.

scholarly journals Clinical associations of proinflammatory cytokines, oxidative biomarkers and vitamin D levels in systemic lupus erythematosus

Lupus ◽  
2017 ◽  
Vol 26 (14) ◽  
pp. 1517-1527 ◽  
Author(s):  
R Willis ◽  
M Smikle ◽  
K DeCeulaer ◽  
Z Romay-Penabad ◽  
E Papalardo ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Vitamin D ◽  
Disease Activity ◽  
Inflammatory Cytokines ◽  
Lupus Erythematosus ◽  
Cytokine Production ◽  
Oxidized Ldl ◽  
Systemic Lupus ◽  
Vitamin D Levels ◽  
Pro Inflammatory Cytokines

Background The abnormal biological activity of cytokines plays an important role in the pathophysiology of both systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Several studies have highlighted the association of vitamin D and certain pro-inflammatory cytokines with disease activity in SLE. However, there are limited data on the association of vitamin D and antiphospholipid antibodies (aPL) with various proinflammatory biomarkers in these patients and their relative impact on clinical outcomes. Methods The serum levels of several aPL, 25-hydroxy-vitamin D, pro-inflammatory cytokines including IFNα, IL-1β, IL-6, IL-8, IP10, sCD40L, TNFα and VEGF were measured in 312 SLE patients from the Jamaican ( n = 45) and Hopkins ( n = 267) lupus cohorts using commercial Milliplex and ELISA assays. Oxidized LDL/β2glycoprotein antigenic complexes (oxLβ2Ag) and their associated antibodies were also measured in the Jamaican cohort. Healthy controls for oxidative marker and cytokine testing were used. Results Abnormally low vitamin D levels were present in 61.4% and 73.3% of Hopkins and Jamaican SLE patients, respectively. Median concentrations of IP10, TNFα, sCD40L and VEGF were elevated in both cohorts, oxLβ2Ag and IL-6 were elevated in the Jamaican cohort, and IFNα, IL-1β and IL-8 were the same or lower in both cohorts compared to controls. IP10 and VEGF were independent predictors of disease activity, aPL, IP10 and IL-6 were independent predictors of thrombosis and IL-8, and low vitamin D were independent predictors of pregnancy morbidity despite there being no association of vitamin D with pro-inflammatory cytokines. Conclusions Our results indicate that aPL-mediated pro-inflammatory cytokine production is likely a major mechanism of thrombus development in SLE patients. We provide presumptive evidence of the role IL-8 and hypovitaminosis D play in obstetric pathology in SLE but further studies are required to characterize the subtle complexities of vitamin D’s relationship with cytokine production and disease activity in these patients.

scholarly journals Paeoniflorin reduces the inflammatory response of THP-1 cells by up‐regulating microRNA-124

2021 ◽  
Author(s):  
Danyun Huang ◽  
Zhijun Li ◽  
Yue Chen ◽  
Yan Fan ◽  
Tao Yu
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Flow Cytometry ◽  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Functional Recovery ◽  
Lupus Erythematosus ◽  
Biological Functions ◽  
Rt Pcr ◽  
Systemic Lupus ◽  
Tnf Α

Abstract Background The activation of macrophages and the release of inflammatory cytokines are the main reasons for the progress of systemic lupus erythematosus (SLE). MicroRNA (miRNA)-124 is involved in the regulation of macrophages and is a key regulator of inflammation and immunity. Objective To explore whether paeoniflorin (PF) regulates the biological functions of macrophages depends on miR-124. Methods RT-PCR, WB, ELISA, CCK-8 and flow cytometry were used to evaluate that PF regulated the biological functions of THP-1 cells through miR-124. Results PF significantly inhibited the proliferation while promotes the apoptosis of THP-1 cells, and inhibited the release of IL-6, TNF-α and IL-1βin THP-1 cells. RT-PCR results shown that PF up-regulated the expression of miR-124 in THP-1 cells. Functional recovery experiments showed that compared with the LPS + mimic-NC group, LPS + miR-124 mimic significantly inhibited the proliferation and the release of IL-6, TNF-α and IL-1β, but promoted the apoptosis of THP-1 cells. In addition, compared with the LPS + PF + inhibitor-NC group, LPS + PF + miR-124 inhibitor significantly promoted the proliferation and the release of IL-6, TNF-α and IL-1β, but inhibited the apoptosis of THP-1 cells. Conclusions By down-regulating miR-124, PF inhibits the proliferation and inflammation of THP-1 cells, and promotes the apoptosis of THP-1 cells.

scholarly journals 4-Octyl Itaconate Activates Nrf2 Signaling to Inhibit Pro-Inflammatory Cytokine Production in Peripheral Blood Mononuclear Cells of Systemic Lupus Erythematosus Patients

2018 ◽  
Vol 51 (2) ◽  
pp. 979-990 ◽  
Author(s):  
Chun Tang ◽  
Xiaohua Wang ◽  
Yingying Xie ◽  
Xiaoyan Cai ◽  
Na Yu ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Nuclear Factor ◽  
Systemic Lupus ◽  
Peripheral Blood Mononuclear ◽  
Human Macrophages ◽  
Tnf Α ◽  
Blood Mononuclear Cells ◽  
Pro Inflammatory Cytokines

Background/Aims: Increased production of multiple pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, plays an essential pathogenic role in the progression of systemic lupus erythematosus (SLE). Recent studies have characterized itaconate as a novel and potent nuclear-factor-E2-related factor 2 (Nrf2) activator that activates Nrf2 signaling by alkylating cysteine residues on Keap1 (Kelch-like ECH-associated protein 1). Methods: THP-1 human macrophages and peripheral blood mononuclear cells (PBMCs) of SLE patients were treated with 4-octyl itaconate (OI). Nrf2 signaling activation was tested by qPCR assay and western blotting. mRNA expression and the production of multiple pro-inflammatory cytokines were tested by qPCR and enzyme-linked immunosorbent assays, respectively. Nuclear factor (NF)-κB activation was tested by the p65 DNA-binding assay. Results: We demonstrated that OI, the cell-permeable derivative of itaconate, induced Keap1-Nrf2 dissociation, Nrf2 protein accumulation, and nuclear translocation, which enabled the transcription and expression of multiple Nrf2-dependentantioxidant enzymes (heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligase modifier subunit) in THP-1 human macrophages. OI also induced significant Nrf2 activation in SLE patient-derived PBMCs. OI pretreatment inhibited mRNA expression and the production of multiple pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in SLE patient-derived PBMCs and lipopolysaccharide (LPS)-activated THP-1 cells. OI potently inhibited NF-κB activation in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Importantly, Nrf2 silencing (by targeted short hairpin RNA) or knockout (by CRISPR/Cas9 gene-editing method) almost abolished OI-induced anti-oxidant and anti-inflammatory actions in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Conclusion: OI activates Nrf2 signaling to inhibit the production of pro-inflammatory cytokines in human macrophages and SLE patient-derived PBMCs. OI and itaconate could have important therapeutic value for the treatment of SLE.

scholarly journals Extracellular Vesicles Tune the Immune System in Renal Disease: A Focus on Systemic Lupus Erythematosus, Antiphospholipid Syndrome, Thrombotic Microangiopathy and ANCA-Vasculitis

2021 ◽  
Vol 22 (8) ◽  
pp. 4194
Author(s):  
Martina Mazzariol ◽  
Giovanni Camussi ◽  
Maria Felice Brizzi
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune System ◽  
Autoimmune Diseases ◽  
Extracellular Vesicles ◽  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Thrombotic Microangiopathy ◽  
Coagulation Cascade ◽  
Renal Diseases ◽  
Systemic Lupus

Extracellular vesicles (EV) are microparticles released in biological fluids by different cell types, both in physiological and pathological conditions. Owing to their ability to carry and transfer biomolecules, EV are mediators of cell-to-cell communication and are involved in the pathogenesis of several diseases. The ability of EV to modulate the immune system, the coagulation cascade, the angiogenetic process, and to drive endothelial dysfunction plays a crucial role in the pathophysiology of both autoimmune and renal diseases. Recent studies have demonstrated the involvement of EV in the control of renal homeostasis by acting as intercellular signaling molecules, mediators of inflammation and tissue regeneration. Moreover, circulating EV and urinary EV secreted by renal cells have been investigated as potential early biomarkers of renal injury. In the present review, we discuss the recent findings on the involvement of EV in autoimmunity and in renal intercellular communication. We focused on EV-mediated interaction between the immune system and the kidney in autoimmune diseases displaying common renal damage, such as antiphospholipid syndrome, systemic lupus erythematosus, thrombotic microangiopathy, and vasculitis. Although further studies are needed to extend our knowledge on EV in renal pathology, a deeper investigation of the impact of EV in kidney autoimmune diseases may also provide insight into renal biological processes. Furthermore, EV may represent promising biomarkers of renal diseases with potential future applications as diagnostic and therapeutic tools.

Expression of High Mobility Group Box Chromosomal Protein 1 and Its Modulating Effects on Downstream Cytokines in Systemic Lupus Erythematosus

2010 ◽  
Vol 37 (4) ◽  
pp. 766-775 ◽  
Author(s):  
JIE LI ◽  
HONGFU XIE ◽  
TING WEN ◽  
HONGBO LIU ◽  
WU ZHU ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Messenger Rna ◽  
Activity Index ◽  
High Mobility ◽  
High Mobility Group ◽  
Chromosomal Protein ◽  
Systemic Lupus ◽  
Tnf Α

Objective.To compare the expression of high mobility group box chromosomal protein 1 (HMGB1) and the modulating effects on its downstream cytokines in patients with systemic lupus erythematosus (SLE) and healthy controls.Methods.HMGB1 concentrations in serum from SLE patients and controls were measured by immunoblot analysis. HMGB1 messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMC) was detected by real-time reverse transcription–polymerase chain reaction. Immunofluorescence assay was employed to examine the translocation of HMGB1 in monocytes after endotoxin stimulation. Release of tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) by PBMC after rHMGB1 stimulation was also measured.Results.Serum HMGB1 levels and HMGB1 mRNA expressions in PBMC were elevated in SLE patients compared with controls. A positive correlation was demonstrated between HMGB1 concentrations and SLE Disease Activity Index. There was an inverse correlation between HMGB1 levels and C4 and C3 concentrations in SLE patients. HMGB1 concentrations were higher in patients with vasculitis and myositis. Lipopolysaccharide stimulated a temporarily elevated release of HMGB1 in SLE patients compared with controls. The pattern and localization of HMGB1 staining in monocytes were similar in both groups. After stimulation with rHMGB1, TNF-α level decreased but IL-6 level increased in SLE patients compared with controls.Conclusion.Our findings suggest that increased serum levels of HMGB1 in SLE may be associated with lupus disease activity. The altered production of TNF-α and IL-6 in response to rHMGB1 stimulation may participate in the disruption of cytokine homeostasis in SLE.

scholarly journals Systemic Lupus Erythematosus Disease: An Overview of the Clinical Approach to Pathogenesis, Diagnosis, and Treatment

2021 ◽  
Vol 4 (2) ◽  
pp. 91-98
Author(s):  
Saurabh Nimesh ◽  
Md. Iftekhar Ahmad ◽  
Shikhka Dhama ◽  
Pradeep Kumar ◽  
Muhammad Akram ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune System ◽  
Chronic Disease ◽  
Lupus Erythematosus ◽  
The Body ◽  
Clinical Approach ◽  
Systemic Lupus Erythematosus Disease ◽  
Systemic Lupus ◽  
Organ Systems ◽  
Novel Approaches

The systemic lupus erythematosus (SLE), commonly known as Lupus, is a rare and complex multisystem autoimmune disease where one’s immune system is overactive, and the body attacks its organ systems. SLE is a historically old disease described already in antiquity; it is an example of a chronic disease with physical, psychological, financial, and social implications for individuals diagnosed. It has inspired medical and basic biological scientists that focus on molecular biology, basic immunology, immunopathology, clinical science, genetics, and epidemiology. The syndrome is real in its existence-although hidden behind obstacles, cumbersome for patients and clinicians, and rebellious for scientists. There is currently no cure for SLE. The goal of treatment is to ease symptoms. This article will review information on the general approach to SLE therapy, focusing on currently approved therapies and novel approaches that might be used in the future.

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