scholarly journals Immunomodulatory effects of mesenchymal stem cell-conditioned media on lipopolysaccharide of Vibrio cholerae as a vaccine candidate

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mahboube Bahroudi ◽  
Bita Bakhshi ◽  
Sara Soudi ◽  
Shahin Najar-peerayeh
Keyword(s):  
Vibrio Cholerae ◽  
Vaccine Candidate ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Mouse Serum ◽  
High Morbidity ◽  
Immunomodulatory Effects ◽  
Tnf Α ◽  
Improvement In Survival ◽  
Full Protection

Abstract Background Vibrio cholerae is the causative agent of cholera, which is commonly associated with high morbidity and mortality, and presents a major challenge to healthcare systems throughout the world. Lipopolysaccharide (LPS) is required for full protection against V. cholerae but can induce inflammation and septic shock. Mesenchymal stem cells (MSCs) are currently used to treat infectious and inflammatory diseases. Therefore, this study aimed to evaluate the immune-modulating effects of the LPS‐MSC‐conditioned medium (CM) on V. cholerae LPS immunization in a murine model. Methods After preconditioning MSCs with LPS, mice were immunized intraperitoneally on days 0 and 14 with the following combinations: LPS + LPS-MSC-CM; detoxified LPS (DLPS) + MSC-CM; LPS + MSC sup; LPS; LPS-MSC-CM; MSC supernatant (MSC sup); and PBS. The mouse serum and saliva samples were collected to evaluate antibody (serum IgG and saliva IgA) and cytokine responses (TNF-α, IL-10, IL-6, TGF-β, IL-4, IL-5, and B-cell activating factor (BAFF)). Results The LPS + LPS-MSC-CM significantly increased total IgG and IgA compared to other combinations (P < 0.001). TNF-α levels, in contrast to IL-10 and TGF-β, were reduced significantly in mice receiving the LPS + LPS-MSC-CM compared to mice receiving only LPS. IL-4, IL-5, and BAFF levels significantly increased in mice receiving increased doses of LPS + LPS-MSC-CM compared to those who received only LPS. The highest vibriocidal antibody titer (1:64) was observed in LPS + LPS-MSC-CM-immunized mice and resulted in a significant improvement in survival in infant mice infected by V. cholerae O1. Conclusions The LPS-MSC-CM modulates the immune response to V. cholerae LPS by regulating inflammatory and anti-inflammatory responses and inducing vibriocidal antibodies, which protect neonate mice against V. cholerae infection.

scholarly journals Dimethyl itaconate inhibits TNF-α induced NF-κB signaling pathway in human epithelial cells

2020 ◽  
Author(s):  
Yalei Zhang ◽  
Xiaobing Deng ◽  
Hao Liang ◽  
Annan Guo ◽  
Kenan Li ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cysteine Residue ◽  
Luciferase Assay ◽  
Dependent Manner ◽  
Nuclear Entry ◽  
Tnf Α ◽  
Novel Strategy ◽  
Dose Dependent ◽  
Dimethyl Itaconate

Abstract Background: Dimethyl itaconate (DMI), a membrane-permeable derivative of itaconate, was found to moderate IL-17-IκBζ-induced skin pathology including psoriasis in mouse experiments . TNF-α induced NF-κB pathway, which controls a variety of immune and inflammatory responses, was also proven to play a crucial role as mediator in psoriasis. However, whether DMI interacts with the TNF-α induced NF-κB pathway remains unclear. Results: Here we show that DMI inhibits TNF-α induced NF-κB transcriptional activities in dose-dependent manner in several human cell lines using dual luciferase assay and blocks the NF-κB nuclear entry. Moreover, DMI potently inhibits IKKβ dependent phosphorylation and degradation of IκBα in TNF-α induced activation of NF-κB pathway. We also demonstrate that DMI covalently binds to cysteine residue in IKKβ, a key regulator in NF-κB pathway, to suppress IKKβ activation and inhibit the canonical NF-κB pathway. Conclusion Our study presents a new mechanism for DMI as an anti-inflammatory agent that may have therapeutic potentials in treating NF-κB related human inflammatory diseases. Our results also suggest that itaconate produced by endogenous IRG1 may regulate NF-κB at post translation modification level, and the IRG1-itaconate-NF-κB axis could be targeted as a novel strategy for the treatment of IRG1-NF-κB mediated diseases.

scholarly journals COVID-19 Severity in Obesity: Leptin and Inflammatory Cytokine Interplay in the Link Between High Morbidity and Mortality

2021 ◽  
Vol 12 ◽  
Author(s):  
Radheshyam Maurya ◽  
Prince Sebastian ◽  
Madhulika Namdeo ◽  
Moodu Devender ◽  
Arieh Gertler
Keyword(s):  
Inflammatory Cytokine ◽  
Inflammatory Responses ◽  
Cytokine Secretion ◽  
Severe Illness ◽  
High Morbidity ◽  
Adaptive Responses ◽  
Chronic Inflammatory Condition ◽  
Tnf Α ◽  
Antigen Presenting ◽  
Plasma Leptin

Obesity is one of the foremost risk factors in coronavirus infection resulting in severe illness and mortality as the pandemic progresses. Obesity is a well-known predisposed chronic inflammatory condition. The dynamics of obesity and its impacts on immunity may change the disease severity of pneumonia, especially in acute respiratory distress syndrome, a primary cause of death from SARS-CoV-2 infection. The adipocytes of adipose tissue secret leptin in proportion to individuals’ body fat mass. An increase in circulating plasma leptin is a typical characteristic of obesity and correlates with a leptin-resistant state. Leptin is considered a pleiotropic molecule regulating appetite and immunity. In immunity, leptin functions as a cytokine and coordinates the host’s innate and adaptive responses by promoting the Th1 type of immune response. Leptin induced the proliferation and functions of antigen-presenting cells, monocytes, and T helper cells, subsequently influencing the pro-inflammatory cytokine secretion by these cells, such as TNF-α, IL-2, or IL-6. Leptin scarcity or resistance is linked with dysregulation of cytokine secretion leading to autoimmune disorders, inflammatory responses, and increased susceptibility towards infectious diseases. Therefore, leptin activity by leptin long-lasting super active antagonist’s dysregulation in patients with obesity might contribute to high mortality rates in these patients during SARS-CoV-2 infection. This review systematically discusses the interplay mechanism between leptin and inflammatory cytokines and their contribution to the fatal outcomes in COVID-19 patients with obesity.

Load Down-Regulates TNF-Alpha Induced Cartilage Degradation in Part Through NF-KB and P38 Pathways

2007 ◽  
Author(s):  
Valerie M. Wolfe ◽  
Seonghun Park ◽  
Marjana Tomic ◽  
Peter A. Torzilli ◽  
C. T. Christopher Chen
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Tensile Load ◽  
Cartilage Degradation ◽  
Acute Injury ◽  
Cyclic Compression ◽  
Tnf Α ◽  
Necrosis Factor ◽  
Pro Inflammatory Cytokines

Pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), can induce cartilage degradation after acute injury or in inflammatory diseases [1,2,3,7]. The degradative events are coordinated through the elevation and activation of two classes of enzymes, namely matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS-4 and −5) [1,6]. Prior studies suggested that pro-inflammatory responses induced by IL-1β can be inhibited by tensile load [2] and more recently by cyclic compression [8]. It is, however, not clear whether load affects other cytokines, such as TNF-α. TNF-α is known to bind its receptor (TNFR1) to cause a cascade that ends with degradation of an inhibitor, IκBα, and release of the transcription factor NF-κB [3]. The actions of TNF-α are also known to be affected by at least three NF-κB independent pathways including the p38, ERK, and JNK pathways [4]. The objective of this study was to determine whether cyclic compression could affect TNF-α induced cartilage degradation and to determine the roles of p38, ERK, and JNK pathways in TNF-induced cartilage degradation. We hypothesized that cyclic loading would inhibit the degradative effects caused by TNF-α.

scholarly journals Protective effect of simvastatin in the cyclophosphamide-induced hemohrragic cystitis in rats

2010 ◽  
Vol 25 (1) ◽  
pp. 43-46 ◽  
Author(s):  
Anna Carolina Batista Dantas ◽  
Francisco Fábio de Araújo Batista-Júnior ◽  
Larissa Freitas Macedo ◽  
Mariana Noronha Castro Mendes ◽  
Ítalo Medeiros Azevedo ◽  
...  
Keyword(s):  
Wistar Rats ◽  
Inflammatory Diseases ◽  
Hemorrhagic Cystitis ◽  
Antineoplastic Agent ◽  
Kidney Injury ◽  
Immunomodulatory Effects ◽  
Tnf Α ◽  
Microscopic Evaluation ◽  
Plasma Cytokines ◽  
Male Wistar Rats

PURPOSE: Cyclophosphamide (CYP) is an antineoplastic agent used for the treatment of many neoplastic and inflammatory diseases. Hemorrhagic cystitis is a frequent side effect of CYP. Several studies show that simvastatin has important pleiotropic (anti-inflammatory and immunomodulatory) effects. The purpose of the study was to investigate the effect of simvastatin on bladder, ureter and kidney injury caused by CYP. METHODS: Adult male Wistar rats were randomly divided into three groups. The CYP/SIM group received simvastatin microemulsion by gavage during 7 days (10 mg/kg body wt) before the administration of CYP and the CYP/SAL group rats received saline 0.9%. The control rats were not treated. After that, all rats were treated with a single dose of CYP 200 mg/kg body wt intraperitoneally. The rats were killed 24 h after CYP administration. Plasma cytokines (TNF-α, IL-1β, IL-6) were measured by ELISA. Macro and light microscopic study was performed in the bladder, kidney and ureter. RESULTS: In the bladders of CYP/SIMV treated rats edema of lamina propria with epithelial and sub-epithelial hemorrhage were lower than in CYP/SAL treated rats. The scores for macroscopic and microscopic evaluation of bladder and ureter were significantly lower in CYP/SIMV rats than in CYP/SAL rats. The kidney was not affected. The expression of TNF-α, IL-1β and IL-6 was significatly lower in CF/SINV rats (164.8±22, 44.8±8 and 52.4±13) than in CF/SAL rats (378.5±66, 122.9±26 e 123.6±18), respectively. CONCLUSION: The results of the current study suggest that simvastatin pretreatment attenuated CYP-induced urotelium inflammation and decreased the activities of cytokines.

scholarly journals Construction and Evaluation of a Safe, Live, Oral Vibrio cholerae Vaccine Candidate, IEM108

2003 ◽  
Vol 71 (10) ◽  
pp. 5498-5504 ◽  
Author(s):  
Weili Liang ◽  
Shixia Wang ◽  
Fenggang Yu ◽  
Lijuan Zhang ◽  
Guoming Qi ◽  
...  
Keyword(s):  
Vibrio Cholerae ◽  
Protective Antigen ◽  
Vaccine Candidate ◽  
Rabbit Model ◽  
Housekeeping Gene ◽  
Cholera Vaccine ◽  
Oral Cholera Vaccine ◽  
Toxigenic Strains ◽  
El Tor ◽  
Full Protection

ABSTRACT IEM101, a Vibrio cholerae O1 El Tor Ogawa strain naturally deficient in CTXΦ, was previously selected as a live cholera vaccine candidate. To make a better and safer vaccine that can induce protective immunity against both the bacteria and cholera toxin (CT), a new vaccine candidate, IEM108, was constructed by introducing a ctxB gene and an El Tor-derived rstR gene into IEM101. The ctxB gene codes for the protective antigen CTB subunit, and the rstR gene mediates phage immunity. The stable expression of the two genes was managed by a chromosome-plasmid lethal balanced system based on the housekeeping gene thyA. Immunization studies indicate that IEM108 generates good immune responses against both the bacteria and CT. After a single-dose intraintestinal vaccination with 109 CFU of IEM108, both anti-CTB immunoglobulin G and vibriocidal antibodies were detected in the immunized-rabbit sera. However, only vibriocidal antibodies are detected in rabbits immunized with IEM101. In addition, IEM108 but not IEM101 conferred full protection against the challenges of four wild-type toxigenic strains of V. cholerae O1 and 4 μg of CT protein in a rabbit model. By introducing the rstR gene, the frequency of conjugative transfer of a recombinant El Tor-derived RS2 suicidal plasmid to IEM108 was decreased 100-fold compared to that for IEM101. This indicated that the El Tor-derived rstR cloned in IEM108 was fully functional and could effectively inhibit the El Tor-derived CTXΦ from infecting IEM108. Our results demonstrate that IEM108 is an efficient and safe live oral cholera vaccine candidate that induces antibacterial and antitoxic immunity and CTXΦ phage immunity.

scholarly journals Ceramide Kinase Regulates TNF-α-induced Immune Responses in Human Monocytic Cells

2021 ◽  
Author(s):  
Fatema Al-Rashed ◽  
Zunair Ahmad ◽  
Ashley J Snider ◽  
Reeby Thomas ◽  
Shihab Kochumon ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Monocytic Cells ◽  
Metabolic Inflammation ◽  
Ceramide Kinase ◽  
Hla Dr ◽  
Tnf Α ◽  
Underlying Mechanisms ◽  
Interfering Rna ◽  
Ceramide 1

Abstract Ceramide kinase (CERK) phosphorylates ceramide to produce ceramide-1-phosphate (C1P), which is involved in the development of metabolic inflammation. TNF-α modulates inflammatory responses in monocytes associated with various inflammatory disorders; however, the underlying mechanisms remain not fully understood. Here, we investigated the role of CERK in TNF-α-induced inflammatory responses in monocytes. Our results show that disruption of CERK activity in monocytes either by the chemical inhibitor NVP- 231 or by small interfering RNA (siRNA) results in the defective expression of inflammatory markers including CD11c, CD11b and HLA-DR in response to TNF-α. Our data show that TNF-α upregulates ceramide phosphorylation. Inhibition of CERK in monocytes significantly reduced the secretion of IL-1β and MCP-1. Similar results were observed in CERK deficient cells. Phosphorylation of JNK, p38 and NF-κB resulting from TNF-α stimulation was reduced by inhibition of CERK. Additionally, NF-κB/AP-1 activity was suppressed by the inhibition of CERK. Clinically, obese individuals had higher levels of CERK expression in PBMCs compared to lean individuals, which correlated with TNF-α levels. Taken together, these results suggest that CERK plays a key role in regulating inflammatory responses in human monocytes during TNF-α stimulation. CERK may be a relevant target for developing novel therapies for chronic inflammatory diseases.

scholarly journals Dimethyl itaconate inhibits TNF-α induced NF-κB signaling pathway in human epithelial cells

2019 ◽  
Author(s):  
yalei zhang ◽  
Xiaobing Deng ◽  
Hao Liang ◽  
Kenan Li ◽  
Annan Guo ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cysteine Residue ◽  
Luciferase Assay ◽  
Dependent Manner ◽  
Nuclear Entry ◽  
Tnf Α ◽  
Novel Strategy ◽  
Dose Dependent ◽  
Dimethyl Itaconate

Abstract Background: Dimethyl itaconate (DMI), a membrane-permeable derivative of itaconate, was found to moderate IL-17-IκBζ-induced skin pathology including psoriasis in mouse experiments. TNF-α induced NF-κB pathway, which controls a variety of immune and inflammatory responses, was also proven to play a crucial role as mediator in psoriasis. However, whether DMI interacts with the TNF-α induced NF-κB pathway remains unclear. Results: Here we show that DMI inhibits TNF-α induced NF-κB transcriptional activities in dose-dependent manner in several human cell lines using dual luciferase assay and blocks the NF-κB nuclear entry. Moreover, DMI potently inhibits IKKβ dependent phosphorylation and degradation of IκBα in TNF-α induced activation of NF-κB pathway. We also demonstrate that DMI covalently binds to cysteine residue in IKKβ, a key regulator in NF-κB pathway, to suppress IKKβ activation and inhibit the canonical NF-κB pathway. Conclusion Our study presents a new mechanism for DMI as an anti-inflammatory agent that may have therapeutic potentials in treating NF-κB related human inflammatory diseases. Our results also suggest that itaconate produced by endogenous IRG1 may regulate NF-κB at post translation modification level, and the IRG1-itaconate-NF-κB axis could be targeted as a novel strategy for the treatment of IRG1-NF-κB mediated diseases.

scholarly journals Novel interaction of antioxidant-1 with TRAF4: role in inflammatory responses in endothelial cells

2019 ◽  
Vol 317 (6) ◽  
pp. C1161-C1171
Author(s):  
Archita Das ◽  
Varadarajan Sudhahar ◽  
Masuko Ushio-Fukai ◽  
Tohru Fukai
Keyword(s):  
Endothelial Cells ◽  
High Fat Diet ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Dependent Manner ◽  
Oxygen Species ◽  
High Fat ◽  
Inflammatory Gene Expression ◽  
Tnf Α

NADPH oxidase (NOX)-derived reactive oxygen species (ROS) and copper (Cu), an essential micronutrient, have been implicated in vascular inflammatory diseases. We reported that in proinflammatory cytokine TNF-α-stimulated endothelial cells (ECs), cytosolic Cu chaperone antioxidant-1 (Atox1) functions as a Cu-dependent transcription factor for the NOX organizer p47phox, thereby increasing ROS-dependent inflammatory gene expression. However, the role and mechanism of Atox1 nuclear translocation in inflamed ECs remain unclear. Using enface staining and nuclear fractionation, here we show that Atox1 was localized in the nucleus in inflamed aortas from ApoE−/− mice with angiotensin II infusion on a high-fat diet, while it was found in cytosol in those from control mice. In cultured human ECs, TNF-α stimulation promoted Atox1 nuclear translocation within 15 min, which was associated with Atox1 binding to TNF-α receptor-associated factor 4 (TRAF4) in a Cu-dependent manner. TRAF4 depletion by siRNA significantly inhibited Atox1 nuclear translocation, p47phox expression, and ROS production as well as its downstream VCAM1/ICAM1 expression and monocyte adhesion to inflamed ECs, which were rescued by overexpression of nuclear targeted Atox1. Furthermore, Atox1 colocalized with TRAF4 at the nucleus in TNF-α-stimulated inflamed ECs and vessels. In summary, Cu-dependent Atox1 binding to TRAF4 plays an important role in Atox1 nuclear translocation and ROS-dependent inflammatory responses in TNF-α-stimulated ECs. Thus the Atox1-TRAF4 axis is a novel therapeutic target for vascular inflammatory disease such as atherosclerosis.

scholarly journals Ceramide kinase regulates TNF-α-induced immune responses in human monocytic cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fatema Al-Rashed ◽  
Zunair Ahmad ◽  
Ashley J. Snider ◽  
Reeby Thomas ◽  
Shihab Kochumon ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Monocytic Cells ◽  
Metabolic Inflammation ◽  
Ceramide Kinase ◽  
Hla Dr ◽  
Tnf Α ◽  
Underlying Mechanisms ◽  
Interfering Rna ◽  
Ceramide 1

AbstractCeramide kinase (CERK) phosphorylates ceramide to produce ceramide-1-phosphate (C1P), which is involved in the development of metabolic inflammation. TNF-α modulates inflammatory responses in monocytes associated with various inflammatory disorders; however, the underlying mechanisms remain not fully understood. Here, we investigated the role of CERK in TNF-α-induced inflammatory responses in monocytes. Our results show that disruption of CERK activity in monocytes, either by chemical inhibitor NVP-231 or by small interfering RNA (siRNA), results in the defective expression of inflammatory markers including CD11c, CD11b and HLA-DR in response to TNF-α. Our data show that TNF-α upregulates ceramide phosphorylation. Inhibition of CERK in monocytes significantly reduced the secretion of IL-1β and MCP-1. Similar results were observed in CERK-downregulated cells. TNF-α-induced phosphorylation of JNK, p38 and NF-κB was reduced by inhibition of CERK. Additionally, NF-κB/AP-1 activity was suppressed by the inhibition of CERK. Clinically, obese individuals had higher levels of CERK expression in PBMCs compared to lean individuals, which correlated with their TNF-α levels. Taken together, these results suggest that CERK plays a key role in regulating inflammatory responses in human monocytes during TNF-α stimulation. CERK may be a relevant target for developing novel therapies for chronic inflammatory diseases.

scholarly journals Neutral sphingomyelinase 2 regulates inflammatory responses in monocytes/macrophages induced by TNF-α

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Fatema Al-Rashed ◽  
Zunair Ahmad ◽  
Reeby Thomas ◽  
Motasem Melhem ◽  
Ashley J. Snider ◽  
...  
Keyword(s):  
Small Interfering Rna ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Neutral Sphingomyelinase ◽  
Tnf Α ◽  
Key Enzyme ◽  
Underlying Mechanisms ◽  
Interfering Rna ◽  
Inflammatory Changes ◽  
Ceramide Production

Abstract Obesity is associated with elevated levels of TNF-α and proinflammatory CD11c monocytes/macrophages. TNF-α mediated dysregulation in the plasticity of monocytes/macrophages is concomitant with pathogenesis of several inflammatory diseases, including metabolic syndrome, but the underlying mechanisms are incompletely understood. Since neutral sphingomyelinase-2 (nSMase2: SMPD3) is a key enzyme for ceramide production involved in inflammation, we investigated whether nSMase2 contributed to the inflammatory changes in the monocytes/macrophages induced by TNF-α. In this study, we demonstrate that the disruption of nSMase activity in monocytes/macrophages either by chemical inhibitor GW4869 or small interfering RNA (siRNA) against SMPD3 results in defects in the TNF-α mediated expression of CD11c. Furthermore, blockage of nSMase in monocytes/macrophages inhibited the secretion of inflammatory mediators IL-1β and MCP-1. In contrast, inhibition of acid SMase (aSMase) activity did not attenuate CD11c expression or secretion of IL-1β and MCP-1. TNF-α-induced phosphorylation of JNK, p38 and NF-κB was also attenuated by the inhibition of nSMase2. Moreover, NF-kB/AP-1 activity was blocked by the inhibition of nSMase2. SMPD3 was elevated in PBMCs from obese individuals and positively corelated with TNF-α gene expression. These findings indicate that nSMase2 acts, at least in part, as a master switch in the TNF-α mediated inflammatory responses in monocytes/macrophages.

Sign in / Sign up

Export Citation Format

Share Document