scholarly journals Tocilizumab Induces IL-10-Mediated Immune Tolerance in Invasive Candidiasis

2021 ◽  
Vol 7 (8) ◽  
pp. 656
Author(s):  
Zhaohong Tan ◽  
Michelle Meng Huang Mok ◽  
Win Mar Soe ◽  
Thomas Paulraj Thamboo ◽  
Jessamine Geraldine Goh ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Invasive Candidiasis ◽  
T Regulatory Cells ◽  
Fungal Infections ◽  
Adverse Outcomes ◽  
Term Survival ◽  
Inflammatory Conditions ◽  
Tnf Α ◽  
Plasmacytoid Dcs

The existence of a hyperinflammatory state has been observed in patients with invasive fungal infections (IFI). It is being postulated whether morbidity from IFI may, in part, be a consequence of an unnecessarily prolonged or exaggerated proinflammatory immune response including interleukin 6 (IL-6) post-infection, in a host with dysregulated or compromised immunity. This, in turn, induces collateral host injury at the tissue and organ level, leading to adverse outcomes. Tocilizumab has become widely used as an immunomodulator in the treatment of inflammatory conditions. Here, we evaluated the use of tocilizumab to curb post-infective inflammatory flare in the setting of an in-vivo mouse model for invasive candidiasis. Following Candida infection, the tocilizumab-treated mice showed improved short-term survival compared with the saline-treated control mice. There was a reduced inflammatory response mounted by the host, coupled with reduced IL-6 but increased IL-10 levels. TNF-α and IFN-γ responses were not affected. Tocilizumab facilitated immune tolerance by selectively inducing IL-10, producing CD8α+ conventional dendritic cells (DCs) and peripheral T-regulatory cells, over CD11b+ conventional DCs and plasmacytoid DCs. We demonstrate here the sequelae from immunomodulatory manipulation and the basis whereby the use of monoclonal antibodies may be further explored in IFI.

scholarly journals Inhibition of Alk signaling promotes the induction of human salivary-gland-derived organoids

2020 ◽  
Vol 13 (9) ◽  
pp. dmm045054 ◽  
Author(s):  
Shohei Yoshimoto ◽  
Junko Yoshizumi ◽  
Hiromasa Anzai ◽  
Koichiro Morishita ◽  
Kazuhiko Okamura ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Fungal Infections ◽  
Disease Model ◽  
Good Health ◽  
Functional Changes ◽  
Human Salivary Gland ◽  
Saliva Secretion ◽  
Tnf Α

ABSTRACTHyposalivation and xerostomia are the cause of several morbidities, such as dental caries, painful mucositis, oral fungal infections, sialadenitis and dysphagia. For these reasons, preservation of normal saliva secretion is critical for the maintenance of functionally normal oral homeostasis and for keeping good health. Several strategies for restoring salivary gland function have been reported, from different points of view, based on the use of salivary-gland-derived epithelial stem/progenitor cells and tissue engineering approaches to induce organoids that mimic in vivo salivary glands. In this study, we clarified that inhibition of activin receptor-like kinase (Alk) signaling was essential for the induction of human salivary-gland-derived organoids, and demonstrated the usefulness of such organoids as an inflammatory disease model. In inflammatory conditions like sialadenitis, in general, pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α, also known as TNF) are upregulated, but their function is still unclear. In our established human salivary-gland-derived organoid culture system, we successfully induced organoid swelling by stimulation with carbachol, a non-selective cholinergic agonist, and forskolin, an activator of cystic fibrosis transmembrane conductance regulator (CFTR). Furthermore, we found that this organoid swelling was inhibited by TNF-α. From these results, we could clarify the inhibitory function of TNF-α on saliva secretion in vitro. Thus, our established human salivary-gland-derived organoids would be useful for in vitro analyses of the morphological and functional changes involved in salivary gland dysfunctions in several research fields, such as pathobiology, inflammation and regenerative medicine.This article has an associated First Person interview with the first author of the paper.

Immunological investigations of oligoethylene glycols functionalized with desaminotyrosine and desaminotyrosyltyrosine

2013 ◽  
Vol 1569 ◽  
pp. 9-14 ◽  
Author(s):  
Konstanze K. Julich-Gruner ◽  
Toralf Roch ◽  
Nan Ma ◽  
Axel T. Neffe ◽  
Andreas Lendlein
Keyword(s):  
Human Blood ◽  
High Concentration ◽  
Inflammatory Conditions ◽  
Tnf Α ◽  
High Concentrations ◽  
Pharmaceutical Agents ◽  
Immunological Evaluation ◽  
Necrosis Factor

ABSTRACTBiomaterials require thorough in vitro testing before being applied in vivo. Unwanted contaminations of biomaterials but also their intrinsic properties can cause uncontrolled immune response leading to severe consequences for the patient. Therefore, immunological evaluation of materials for biomedical applications is mandatory before entering clinical application. In order to introduce physical netpoints, the aromatic compounds desaminotyrosine (DAT) and desaminotyrosyl-tyrosine (DATT) were successfully used to functionalize linear and star-shaped oligoethylene glycol (lOEG and sOEG) as previously described. The materials showed properties of surfactants and have potential to be used for solubilization of lipophilic drugs in water. Furthermore, the materials are susceptible for H2O2 degradation as determined by MALDI-ToF MS analyses. This is important for potential in vivo applications, as macrophages can release reactive oxygen species (ROS) under inflammatory conditions. As it is known that surfactant solutions of high concentration can lead to cell lysis, the effects of OEG-DAT(T) solutions on murine RAW macrophages were investigated. Even at highest OEG-DAT(T) concentration of 1000 µg·mL-1 the viability of the RAW cells was not significantly impaired. Additionally, the polymers were incubated with whole human blood and the production of inflammatory cytokines such as the tumor necrosis factor (TNF)-α and interleukin (IL)-6 was determined. Only at high concentrations, the OEG-DAT(T) solution induced low levels of TNF-α and IL-6, indicating that a mild inflammatory reaction could be expected when such high OEG-DAT(T) concentrations are applied in vivo. Similarly, the OEG-DAT(T) solution did not induce ROS in monocytes and neutrophils after incubation with whole human blood. Conclusively, the data presented here demonstrate that OEG-DAT(T) do not lead to a substantial activation of the innate immune mechanisms and could therefore be investigated for solubilizing pharmaceutical agents.

Glycoprotein IIb/Iiia Antagonist Could Reduce the Inflammatory Factors IL-6, IL-1β, TNF-α of Atherosclerosis Rabbits in Vivo

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5451-5451
Author(s):  
Songmei Yin ◽  
Shuangfeng Xie ◽  
Yiqing Li ◽  
Danian Nie ◽  
Liping Ma ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Inflammatory Factors ◽  
Saline Control ◽  
Control Group ◽  
Rabbit Plasma ◽  
Term Survival ◽  
Tnf Α ◽  
Full Dosage ◽  
Time Point

Abstract Background: Glycoprotein (GP) IIb/IIIa antagonists have been widely used in clinical practice. It had been demonstrated that although GPIIb/IIIa antagonists could reduce 30%~ 50% ischemic events around coronary artery intervention therapy, it had only limited effects on the long term survival. We want to explore the effects of GPIIb/IIIa antagonists besides inhibiting platelet aggregation. So we observed the effects of tirofiban (a GP IIb/IIIa antagonist) in vivo. Design: the atherosclerosis model rabbits were divided into 4 groups. Each group got a 1.7ml/h nature saline (control group), 3.125mg/L, 12.5 mg/L or 50mg/L tirofiban continuous intravenous injection for 48 hours respectively. Platelet aggregation maximum (PAG(M)), plasma interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α were measured at 0 hour, 12th hour, 24th hour and 48th hour time point. Results: In vivo, compare to the value at 0 hour, the PAG(M) didn’t change significantly at the 12th hour, 24th hour and 48th hour time point in the control group and 3.125mg/L tirofiban group. While the PAG(M) was reduced at the 12th hour, 24th hour and 48th hour time point in the 12.5mg/L and 3.125mg/L tirofiban group. About the inflammatory factors, in control group, compare to the index at 0 hour, plasma IL-1β, IL-6 and TNF-α concentration were all increased significantly at the 12th hour time point. In the 3.125mg/L tirofiban group, the plasma IL-1β and IL-6 concentration elevated significantly at the 24th hour time point. In the 12.5mg/L tirofiban group, the plasma IL-6 and TNF-α concentration at 24th hour time point, the plasma IL-1β, IL-6 and TNF-α concentration at 48th hour time point were all decreased significantly. In 50mg/L tirofiban group, the plasma IL-6 concentration at 12th hour time point, the plasma IL-1β, IL-6 and TNF-α concentration at 24th hour and 48th hour time point were all decreased. At 0 hour, plasma IL-1β, IL-6 and TNF-α concentration had no difference among the 4 groups (IL-1β PANOVA=0.954, IL-6 PANOVA=0.954, TNF-α PANOVA=0.954. n=5). While at 12 hour, 24 hour or 48 hour time points, among the 4 groups, the index value of the IL-1β, IL-6 and TNF-α decreased along with the increase of the tirofiban concentration (PANOVA<0.01. n=5). Conclusion: In vivo, full dosage tirofiban could inhibit PAG(M), decrease the production of rabbit plasma IL-6, IL-1β and TNF-α. While little dosage tirofiban (≤3.125mg/L) had no effect on PAG(M), could not decrease the production of rabbit plasma IL-6, IL-1β and TNF-α. GP IIb/IIIa antagonist could reduce the inflammatory factors in full dosage.

Expression of Protein S in the Murine Heart and Cultured Mouse Cardiomyocytes Is Down-regulated by Cytokines

2001 ◽  
Vol 86 (08) ◽  
pp. 623-629 ◽  
Author(s):  
Takayoshi Shimokawa ◽  
Eriko Yamafuji ◽  
Tetsuhito Kojima ◽  
Hidehiko Saito ◽  
Koji Yamamoto
Keyword(s):  
Protein C ◽  
Interleukin 1 ◽  
Activated Protein C ◽  
Protein S ◽  
Suppressive Effect ◽  
Inflammatory Conditions ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

SummaryProtein S (PS), a co-factor of activated protein C, is a vitamin K-dependent anticoagulant protein and is known to be produced extrahepatically. In the present study, the concentration of PS mRNA was determined tissue by tissue in the mouse, and it was high in lung, adrenal and heart as well as in liver. We further investigated the effects of lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α), and interleukin-1 (IL-1) on the PS mRNA expression in murine tissues in vivo. Although LPS and TNF-α significantly decreased the expression level of PS mRNA in all tissues examined (e.g., lung, liver, heart, and kidney) and the PS antigen level in plasma, the suppressive effect of IL-1 on PS gene expression was limited to heart. More specifically, considerable amounts of PS mRNA and antigen were expressed in a cultured mouse cardiomyocyte cell line, and again, treatment with IL-1 decreased the PS expression in these cells. These observations raise a possibility that the expression of cardiac PS may contribute to the regional anticoagulant potential in heart, and suggest that the decreased PS expression by cytokines may result in an increase in the systemic and/or regional prothrombotic potential under inflammatory conditions.

Anti-β2 Glycoprotein I Antibodies Cause Inflammation and Recruit Dendritic Cells in Platelet Clearance

2001 ◽  
Vol 86 (11) ◽  
pp. 1257-1263 ◽  
Author(s):  
Attilio Bondanza ◽  
Angelo Manfredi ◽  
Valérie Zimmermann ◽  
Matteo Iannacone ◽  
Angela Tincani ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Inflammatory Responses ◽  
Glycoprotein I ◽  
Activated Platelets ◽  
Tnf Α ◽  
Per Se ◽  
Antigen Presenting ◽  
Antiinflammatory Cytokine

SummaryScavenger phagocytes are mostly responsible for the in vivo clearance of activated or senescent platelets. In contrast to other particulate substrates, the phagocytosis of platelets does not incite pro-inflammatory responses in vivo. This study assessed the contribution of macrophages and dendritic cells (DCs) to the clearance of activated platelets. Furthermore, we verified whether antibodies against the β2 Glycoprotein I (β2GPI), which bind to activated platelets, influence the phenomenon. DCs did not per se internalise activated platelets. In contrast, macrophages efficiently phagocytosed platelets. In agreement with the uneventful nature of the clearance of platelets in vivo, phagocytosing macrophages did not release IL-1β, TNF-α or IL-10. β2GPI bound to activated platelets and was required for their recognition by anti-ββ2GPI antibodies. DCs internalised platelets opsonised by anti-ββ2GPI antibodies. The phagocytosis of opsonised platelets determined the release of TNF-α and IL-1β by DCs and macrophages. Phagocytosing macrophages, but not DCs, secreted the antiinflammatory cytokine IL-1β0. We conclude that anti-ββ2GPI antibodies cause inflammation during platelet clearance and shuttle platelet antigens to antigen presenting DCs.

Tinospora cordifolia Aqueous Extract Alleviates Cyclophosphamide- Induced Immune Suppression, Toxicity and Systemic Candidiasis in Immunosuppressed Mice: In vivo Study in Comparison to Antifungal Drug Fluconazole

2019 ◽  
Vol 20 (12) ◽  
pp. 1055-1063 ◽  
Author(s):  
Faris Alrumaihi ◽  
Khaled S. Allemailem ◽  
Ahmad Almatroudi ◽  
Mohammed A. Alsahli ◽  
Arif Khan ◽  
...  
Keyword(s):  
Survival Rate ◽  
Aqueous Extract ◽  
Survival Data ◽  
Tinospora Cordifolia ◽  
Systemic Candidiasis ◽  
Organ Index ◽  
Tnf Α ◽  
Fungal Load ◽  
Enhanced Secretion

Objective: The present study was aimed to evaluate the effect of the aqueous extract of Tinospora cordifolia (AETC) against cyclophosphamide-induced immunosuppression and systemic Candida albicans infection in a murine model. Methods: The protective effect of AETC against cyclophosphamide-induced leukopenia was evaluated by quantitative and qualitative analysis of the leukocytes. The immune-stimulating potential of AETC on macrophages was assessed by determining the levels of secreted cytokines. To determine the direct antifungal activity, AETC or fluconazole was administered to C. albicans infected mice. The efficacy of treatment was assessed by determining the survival rate, kidney fungal burden, the organ index and liver inflammation parameters. Results: Cyclophosphamide administration resulted in substantial depletion of leukocytes, whereas AETC treatment induced the recovery of leukocytes in cyclophosphamide-injected mice. Moreover, AETC treatment of macrophages resulted in enhanced secretion of IFN-γ, TNF-α and IL-1β. C. albicans infected mice treated with AETC at the doses of 50 and 100 mg/kg exhibited 40% and 60% survival rate, whereas the mice treated with fluconazole at a dose of 50 mg/kg showed 20% survival rate. Like survival data, the fungal load was found to be the lowest in the kidney tissues of mice treated with AETC at a dose of 100 mg/kg. Interestingly, mice infected with C. albicans demonstrated improvement in the organ indices and liver functioning after AETC treatment. Conclusion: These results suggest that AETC may potentially be used to rejuvenate the weakened immune system and eliminate systemic candidiasis in mice.

Increased Circulatory Extrarenal 1α,25-Dihydroxyvitamin D3 in Bilaterally Nephrectomized Rats

2020 ◽  
Vol 20 (9) ◽  
pp. 1523-1530
Author(s):  
Murat Dabak ◽  
Durrin O. Dabak ◽  
Tuncay Kuloglu ◽  
Ersoy Baydar ◽  
Hakan Bulut ◽  
...  
Keyword(s):  
Immune Cells ◽  
Low Dose ◽  
Systemic Circulation ◽  
Bilateral Nephrectomy ◽  
Dihydroxyvitamin D3 ◽  
Hydroxyvitamin D ◽  
Inflammatory Conditions ◽  
Calcium Phosphorus ◽  
25 Hydroxyvitamin D

Background: Extrarenal 1α,25-dihydroxyvitamin D3 (1,25-D) locally produced by immune cells plays crucial roles in the regulation of the immune system. However, in vivo status of extrarenal 1,25-D and 25-hydroxyvitamin D (25-D) in acute inflammatory conditions are unknown. Objective: The aim of this study was to determine the extrarenal 1,25-D level in circulation in bilaterally nephrectomized rats, induced by low-dose lipopolysaccharide (LPS). Methods: Renal 1,25-D synthesis was terminated through bilateral nephrectomy in rats. The rats received intraperitoneal LPS (50 μg/kg BW) three times and the experiment was ended 24 hours after nephrectomy. Serum 1,25-D, 25-D, calcium, phosphorus, intact parathyroid hormone, and calcitonin levels were measured and immunohistochemistry was applied to detect the sources of extrarenal 1,25- D synthesis. Results: Circulatory 1,25-D concentration remarkably increased in both LPS-treated and non-treated bilaterally nephrectomized rats. Elevated circulatory 1,25-D did not have hypercalcemic endocrinal effects. The increased 1,25-D level also resulted in a concurrent rapid and dramatic depletion of circulatory 25-D. Conclusions: Extrarenal 1,25-D could enter into the systemic circulation and, therefore, might have systemic effects besides its autocrine and paracrine functions.

scholarly journals N-Terminomics Strategies for Protease Substrates Profiling

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4699
Author(s):  
Mubashir Mintoo ◽  
Amritangshu Chakravarty ◽  
Ronak Tilvawala
Keyword(s):  
Mass Spectrometry ◽  
Protease Activity ◽  
Viral Infections ◽  
Mass Spectrometry Analysis ◽  
Post Translational Modification ◽  
Spectrometry Analysis ◽  
Physiological Conditions ◽  
Inflammatory Conditions ◽  
Biological Mixtures

Proteases play a central role in various biochemical pathways catalyzing and regulating key biological events. Proteases catalyze an irreversible post-translational modification called proteolysis by hydrolyzing peptide bonds in proteins. Given the destructive potential of proteolysis, protease activity is tightly regulated. Dysregulation of protease activity has been reported in numerous disease conditions, including cancers, neurodegenerative diseases, inflammatory conditions, cardiovascular diseases, and viral infections. The proteolytic profile of a cell, tissue, or organ is governed by protease activation, activity, and substrate specificity. Thus, identifying protease substrates and proteolytic events under physiological conditions can provide crucial information about how the change in protease regulation can alter the cellular proteolytic landscape. In recent years, mass spectrometry-based techniques called N-terminomics have become instrumental in identifying protease substrates from complex biological mixtures. N-terminomics employs the labeling and enrichment of native and neo-N-termini peptides, generated upon proteolysis followed by mass spectrometry analysis allowing protease substrate profiling directly from biological samples. In this review, we provide a brief overview of N-terminomics techniques, focusing on their strengths, weaknesses, limitations, and providing specific examples where they were successfully employed to identify protease substrates in vivo and under physiological conditions. In addition, we explore the current trends in the protease field and the potential for future developments.

scholarly journals Pirfenidone attenuates synovial fibrosis and postpones the progression of osteoarthritis by anti-fibrotic and anti-inflammatory properties in vivo and in vitro

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Qilu Wei ◽  
Ning Kong ◽  
Xiaohui Liu ◽  
Run Tian ◽  
Ming Jiao ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cell Counting ◽  
Enzyme Linked Immunosorbent Assay ◽  
Fast Green ◽  
Expression Levels ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Safranin O ◽  
Tgf Β1

Abstract Background Osteoarthritis (OA) is a disease of the entire joint involving synovial fibrosis and inflammation. Pathological changes to the synovium can accelerate the progression of OA. Pirfenidone (PFD) is a potent anti-fibrotic drug with additional anti-inflammatory properties. However, the influence of PFD on OA is unknown. Methods Proliferation of human fibroblast-like synoviocytes (FLSs) after treatment with TGF-β1 or PFD was evaluated using a Cell Counting Kit-8 assay and their migration using a Transwell assay. The expression of fibrosis-related genes (COL1A1, TIMP-1, and ACTA-2) and those related to inflammation (IL-6 and TNF-α) was quantified by real-time quantitative PCR. The protein expression levels of COL1A1, α-SMA (coded by ACTA-2), IL-6 and TNF-α were measured by enzyme-linked immunosorbent assay. A rabbit model of OA was established and then PFD was administered by gavage. The expression of genes related to fibrosis (COL1A1, TIMP-1, and ADAM-12) and inflammation (IL-6 and TNF-α) was measured using RNA extracted from the synovium. Synovial tissue was examined histologically after staining with H&E, Masson’s trichrome, and immunofluorescence. Synovitis scores, the volume fraction of collagen, and mean fluorescence intensity were calculated. Degeneration of articular cartilage was analyzed using a Safranin O-fast green stain and OARSI grading. Results The proliferation of FLSs was greatest when induced with 2.5 ng/ml TGF-β1 although it did not promote their migration. Therefore, 2.5 ng/ml TGF-β1 was used to stimulate the FLSs and evaluate the effects of PFD, which inhibited the migration of FLSs at concentrations as low as 1.0 mg/ml. PFD decreased the expression of COL1A1 while TGF-β1 increased both mRNA and protein expression levels of IL-6 but had no effect on α-SMA or TNF-α expression. PFD decreased mRNA expression levels of COL1A1, IL-6, and TNF-α in vivo. H&E staining and synovitis scores indicated that PFD reduced synovial inflammation, while Masson’s trichrome and immunofluorescence staining suggested that PFD decreased synovial fibrosis. Safranin O-Fast Green staining and the OARSI scores demonstrated that PFD delayed the progression of OA. Conclusions PFD attenuated synovial fibrosis and inflammation, and postponed the progression of osteoarthritis in a modified Hulth model of OA in rabbits, which was related to its anti-fibrotic and anti-inflammatory properties.

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