scholarly journals MyD88-dependent BCG immunotherapy reduces tumor and regulates tumor microenvironment in bladder cancer murine model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nina M. G. P. de Queiroz ◽  
Fabio V. Marinho ◽  
Ana Carolina V. S. C. de Araujo ◽  
Julia S. Fahel ◽  
Sergio C. Oliveira
Keyword(s):  
Immune Response ◽  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Innate Immune ◽  
Bcg Immunotherapy ◽  
First Line Therapy ◽  
Efficient Immune Response ◽  
Tnf Α ◽  
Immune Pathway ◽  
Inflammatory Macrophages

AbstractBacillus Calmette-Guerin (BCG) is the only FDA approved first line therapy for patients with nonmuscle invasive bladder cancer. The purpose of this study is to better understand the role of innate immune pathways involved in BCG immunotherapy against murine bladder tumor. We first characterized the immunological profile induced by the MB49 mouse urothelial carcinoma cell line. MB49 cells were not able to activate an inflammatory response (TNF-α, IL-6, CXCL-10 or IFN-β) after the stimulus with different agonists or BCG infection, unlike macrophages. Although MB49 cells are not able to induce an efficient immune response, BCG treatment could activate other cells in the tumor microenvironment (TME). We evaluated BCG intratumoral treatment in animals deficient for different innate immune molecules (STING−/−, cGAS−/−, TLR2−/−, TLR3−/−, TLR4−/−, TLR7−/−, TLR9−/−, TLR3/7/9−/−, MyD88−/−, IL-1R−/−, Caspase1/11−/−, Gasdermin-D−/− and IFNAR−/−) using the MB49 subcutaneous mouse model. Only MyD88−/− partially responded to BCG treatment compared to wild type (WT) mice, suggesting a role played by this adaptor molecule. Additionally, BCG intratumoral treatment regulates cellular infiltrate in TME with an increase of inflammatory macrophages, neutrophils and CD8+ T lymphocytes, suggesting an immune response activation that favors tumor remission in WT mice but not in MyD88−/−. The experiments using MB49 cells infected with BCG and co-cultured with macrophages also demonstrated that MyD88 is essential for an efficient immune response. Our data suggests that BCG immunotherapy depends partially on the MyD88-related innate immune pathway.

scholarly journals Type 17 Immune Response Facilitates Progression of Inflammation and Correlates with Cognition in Stable Schizophrenia

Diagnostics ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 926
Author(s):  
Milica M. Borovcanin ◽  
Slavica Minic Janicijevic ◽  
Ivan P. Jovanovic ◽  
Nevena M. Gajovic ◽  
Milena M. Jurisevic ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Serum Levels ◽  
Antipsychotic Therapy ◽  
Necrosis Factor Alpha ◽  
Positive Correlation ◽  
Tnf Α ◽  
Immune Pathway

Dysregulation of the type 17 immune pathway has already been considered in schizophrenia and we previously measured decreased sera values of interleukin (IL)-17 in early stages. We further explored the possible correlation of IL-17 systemic levels with proinflammatory cytokines and cognitive scores and additionally analyzed the percentage of IL-17 producing lymphocytes in peripheral blood of patients with stable schizophrenia. We included 27 patients diagnosed with schizophrenia (F20), after a three-month stable depot antipsychotic therapy (risperidone or paliperidone) and 18 healthy control subjects. Positive and Negative Syndrome Scale of Schizophrenia and the Montreal-Cognitive Assessment (MoCA) were conducted. Sera concentrations of IL-17, IL-6, tumor necrosis factor alpha (TNF-α) and soluble ST2 receptor (sST2) were measured. Flow cytometry and Natural Killer (NK) and T cell analyses were done in 10 patients and 10 healthy controls. Moderate positive correlation was established between IL-17 and TNF-α (r = 0.640; p = 0.001), IL-17 and IL-6 (r = 0.514; p = 0.006), IL-17 and sST2 (r = 0.394; p = 0.042). Furthermore, a positive correlation between the serum levels of IL-17 and MoCA scores was observed, especially with visuospatial and executive functioning, as well as language functioning and delayed recall (p < 0.05). Significantly higher percentage of IL-17 producing CD56+ NK cells was measured in peripheral blood of patients with schizophrenia in remission vs. healthy individuals (p = 0.001). The percentage of CD4+ T cells and CD4+ T cells that produce IL-17 was significantly increased in patients (p = 0.001). This study revealed the involvement of innate type 17 immune response in the progression of inflammation and this could be related to cognitive functioning in stable schizophrenia.

Differential modulation of innate immune response by epinephrine and estradiol

2017 ◽  
Vol 30 (3) ◽  
Author(s):  
Sona Margaryan ◽  
Armenuhi Hyusyan ◽  
Anush Martirosyan ◽  
Shushan Sargsian ◽  
Gayane Manukyan
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Dependent Manner ◽  
Induced Expression ◽  
Short Term Exposure ◽  
Tnf Α ◽  
Vitro Effect ◽  
Dose Dependent

AbstractBackgroundAlthough it is widely accepted that catecholamines and estrogens influence immunity and have consequences for health, their effect on innate immunity (e.g. monocytes and neutrophils) is still not fully investigated.Materials and methodsOur study aimed to analyze the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, monocyte chemoattractant protein (MCP)-1 and IL-8 by whole blood cells following short-term exposure to epinephrine (Epi) and 17β-estradiol (E2) in the presence or absence of lipopolysaccharide (LPS). We also evaluated the in vitro effect of these hormones on expression of β2 integrin (CD11b/CD18) and L-selectin (CD62L) by circulating neutrophils and monocytes in the blood of healthy subjects.ResultsEpi has shown a potential to modulate the production of pro-inflammatory mediators. Its exposure resulted in significantly increased production of IL-8 in a dose-dependent manner. On the contrary, a dose-dependent suppression of LPS-induced production of IL-1β, IL-8, and MCP-1 by Epi was observed. In neutrophils, a modest rise in CD11b expression was observed after Epi exposure. Simultaneously, Epi suppressed LPS-induced expression of CD11b and CD18. In monocytes, Epi suppressed LPS-induced expression of C11b. E2 inhibited LPS-induced TNF-α production and caused a significant decrease in CD62L expression in both cell populations. No significant changes were observed after double exposure of cells with Epi and E2.ConclusionsThus, our results show that Epi and E2 differentially modulate the innate immune response and have a dual effect on cytokine modulation. The findings suggest that the observed immunoregulatory role of Epi and E2 may influence the outcome in endotoxin responses and can be critical in the regulation of inflammatory responses.

Transient membrane recruitment of IRAK-1 in response to LPS and IL-1β requires TNF R1

2008 ◽  
Vol 295 (2) ◽  
pp. C313-C323 ◽  
Author(s):  
Angelia Lockett ◽  
Mark G. Goebl ◽  
Maureen A. Harrington
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Plasma Membrane ◽  
Innate Immune Response ◽  
Cellular Response ◽  
Interleukin 1 ◽  
Innate Immune ◽  
Variable Response ◽  
Membrane Recruitment ◽  
Tnf Α

The transcription factor NF-κB is an essential regulator of the innate immune response that functions as the first line of defense against infections. Activation of the innate immune response by bacterial lipopolysaccharide (LPS) triggers production of tumor necrosis factor-α (TNF-α) followed by interleukin-1 (IL-1). The IL-1 receptor associated kinase-1 (IRAK-1) is an integral component of the LPS, TNF-α, and IL-1 signaling pathways that regulate NF-κB. Thus we hypothesized that IRAK-1 coordinates cellular NF-κB responses to LPS, TNF-α, and IL-1. In contrast to TNF-α where IRAK-1 subcellular localization does not change, treatment with LPS or IL-1 leads to a loss in cytoplasmic IRAK-1 with a coordinate increase in plasma membrane associated modified IRAK-1. In fibroblasts lacking the type 1 TNF-α receptor (TNF R1), IRAK-1 turnover is altered and modification of IRAK-1 in the plasma membrane is decreased in response to LPS and IL-1, respectively. When NF-κB controlled gene expression is measured, fibroblasts lacking TNF R1 are hyperresponsive to LPS, whereas a more variable response to IL-1 is seen. Further analysis of the LPS response revealed that plasma membrane-associated IRAK-1 is found in Toll 4, IL-1, and TNF R1-containing complexes. The data presented herein suggest a model whereby the TNF R1-IRAK-1 interaction integrates the cellular response to LPS, TNF-α, and IL-1, culminating in a cell poised to activate TNF-α-dependent NF-κB controlled gene expression. In the absence of TNF R1-dependent events, exposure to LPS or IL-1 leads to hyperactivation of the inflammatory response.

scholarly journals SIGIRR and TNFAIP3 Are Differentially Expressed in Both PBMC and TNF-α Secreting Cells of Patients With Major Depressive Disorder

2021 ◽  
Vol 12 ◽  
Author(s):  
Chin-Chuen Lin ◽  
Tiao-Lai Huang
Keyword(s):  
Immune Response ◽  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Innate Immune ◽  
Differentially Expressed ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Negative Regulators ◽  
Major Depressive ◽  
Tnf Α

Background: Major depressive disorder (MDD) is associated with the activation of the immune/inflammatory system. TNF-α is associated with MDD and poor treatment response. Toll-like receptors (TLR) are responsible in innate immune response, and is associated with MDD and antidepressant response. Some negative regulators of TLR pathway such as SOCS1, TOLLIP, SIGIRR, TNFAIP3, and MyD88s, are reported to be differentially expressed in the peripheral blood samples of patients of MDD.Methods: We recruited patients with MDD and healthy controls, collect their demographic data, and measured their mRNA levels of negative TLR regulators, using peripheral blood mononuclear cells (PBMC) and isolated TNF-α secreting cells. Clinical symptoms were evaluated using Halmiton Depression Rating Scale (Ham-D). Some patients were evaluated again after 4 weeks of antidepressant treatment.Results: Forty-seven patients with MDD and 52 healthy controls were recruited. Between the PBMC samples of 37 MDD patients and 42 controls, mRNA levels of SOCS1, SIGIRR, TNFAIP3, and MyD88s were significantly different. Between TNF-α secreting cells of 10 MDD patients and 10 controls, mRNA levels of SIGIRR and TNFAIP3 were significantly different. Change of Ham-D score only correlated significantly with TOLLIP mRNA level after treatment.Conclusion: SIGIRR and TNFAIP3, two negative regulators of TLR immune response pathways, were differentially expressed in both PBMC and TNF-α secreting cells of patients with MDD as compared to healthy controls. The negative regulations of innate immune response could contribute to the underlying mechanism of MDD.

Ivig Negatively Regulates LPS-Induced Monocytes Activation Through a Microrna-146a Related Mechanism

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3274-3274
Author(s):  
Lionel Loubaki ◽  
Renée Bazin
Keyword(s):  
Immune Response ◽  
Inflammatory Cytokines ◽  
Small Rna ◽  
Cytokine Production ◽  
Innate Immune ◽  
Human Monocytes ◽  
Monocytic Cells ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Stimulation Of

Abstract Abstract 3274 Background: Cells from the monocytic lineage are known to play a central role in the immune defense against pathogens. In the adaptive immune response, they act as antigen presenting cells to trigger T and B cell responses. Monocytic cells also participate in innate immunity following recognition of pathogen-associated molecular patterns (PAMPs) such as bacterial lipopolysaccharides (LPS), which leads to their activation and release of very potent inflammatory mediators. The innate immune response thus needs to be tightly regulated to control not only its onset, but also its termination in order to avoid excessive inflammation. Recent studies have shown that the differentiation and functions of monocytic cells involve small RNA species, named microRNAs (miRNAs). MiRNAs are 21–23 nucleotide long single strand RNAs, which mainly cause gene silencing by degradation of target mRNAs or by inhibition of translation. Among them, miR-146a has captivated interest as it plays an important role in the negative regulation of acute inflammatory responses during activation of the innate immune system. In fact, it has been shown that miR-146a expression is gradually increased in THP-1 monocytic cells following stimulation with LPS or cytokines (e.g. IL-1β and TNF-α) via a NF-κB dependent pathway. MiR-146a inhibits the expression of IRAK1 and TRAF6 leading to the subsequent suppression of NF-κB activity. Consequently, the expression of NF-κB target genes such as IL-1β, TNF-α and PU.1 is suppressed. Therefore, miR146a controls NF-κB signaling via a negative feedback regulation loop and thus can be considered as an anti-inflammatory mediator. IVIg is a therapeutic preparation of polyclonal human IgG isolated from the plasma of thousands of healthy donors. IVIg is well known for its anti-inflammatory effects on a variety of immune cells and processes. More precisely, it has been shown to abrogate the capacity of monocyte-derived dendritic cells to secrete pro-inflammatory cytokines while increasing the expression of anti-inflammatory cytokines such as IL-10. We thus hypothesize that at least some of the anti-inflammatory effects of IVIg on monocytic cells could be triggered through the modulation of miR-146a expression. Objectives: To evaluate the involvement of miR-146a in the anti-inflammatory effects of IVIg following LPS stimulation of human monocytes. Methods: Human monocytes were obtained from the blood of healthy volunteers and treated with LPS (1 mg/mL) or IVIg (15 mg/mL) alone or alternatively, pretreated with LPS followed by addition of IVIg. Pre-treatment with LPS was done during for 4 h prior to addition of IVIg for 3, 6, 12 and 24 hours. Cells were then recovered and separated in two parts. The first part was used to extract the small RNA fraction of total RNA for miRNA analysis and the second part was used for protein isolation. The miR-146a level was measured by real time PCR while NF-kB and IRF4 protein levels were evaluated by western blotting. Finally, the expression of the transcription factor PU.1 was evaluated by flow cytometry. Results: Our preliminary data revealed that addition of IVIg to LPS-pretreated human monocytes resulted in a significant upregulation of miR-146a expression associated with a significant reduction in NF-κB expression. Furthermore, the expression of the PU.1/IRF4 transcriptional activator complex involved in the stimulation of inflammatory cytokine production was modulated. Indeed, we found that the expression PU.1 was reduced in IVIg-treated cells whereas IRF4 expression was increased, thus promoting the IRF4-mediated cytokine production inhibitory pathway. Conclusion: Our preliminary data suggest that in human monocytes, the anti-inflammatory effects of IVIg may involve miR-146a negative feedback loop regulation of NF-κB activity. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Angiotensin II AT1 blockade reduces the lipopolysaccharide-induced innate immune response in rat spleen

2009 ◽  
Vol 296 (5) ◽  
pp. R1376-R1384 ◽  
Author(s):  
Enrique Sánchez-Lemus ◽  
Julius Benicky ◽  
Jaroslav Pavel ◽  
Ignacio M. Larrayoz ◽  
Jin Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Inflammatory Response ◽  
Protein Expression ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Bacterial Endotoxin ◽  
Ang Ii ◽  
Tnf Α ◽  
Mrna And Protein Expression

ANG II AT1 receptor blockade reduces inflammation in hypertension. To determine whether ANG II AT1 receptor blockers (ARBs) influence the innate immune inflammatory response in normotensive rats, we studied rat plasma and spleen after a 3-day subcutaneous pretreatment with the ARB candesartan followed by a single dose of the bacterial endotoxin LPS (50 μg/kg ip). Peripheral administration of LPS to rodents produced a generalized inflammatory response with increased release of TNF-α, IL-1β, and IL-6 into the circulation. Candesartan pretreatment reduced the LPS-induced release of TNF-α, IL-1β, and IL-6 into the circulation. The red pulp of rat spleen expressed large numbers of AT1 receptors and the LPS receptors Toll-like receptor 4 and CD14. Candesartan administration significantly blocked AT1 receptors. The ARB reduced the LPS-induced upregulation of CD14 gene expression; expression of TNF-α and IL-6 mRNA and protein; expression of IL-1β and IκB-α mRNA; COX-2 mRNA and protein expression and PGE2 concentration; inducible nitric oxide synthase (iNOS) gene and protein expression and iNOS activity; and Nox2 gene expression and 8-isoprostane levels. In addition, candesartan reduced the CD14 protein expression in saline- and LPS-treated rats. Our results suggest that AT1 receptors are essential for the development of the full innate immune response to bacterial endotoxin. The ARB decreased the general peripheral inflammatory reaction to LPS and partially decreased the inflammatory response in the spleen. An unrestricted innate immune response to the bacterial endotoxin may have deleterious effects for the organism and may lead to development of chronic inflammatory disease. We postulate that ARBs may have therapeutic effects on inflammatory conditions.

scholarly journals Kdo Hydrolase Is Required for Francisella tularensis Virulence and Evasion of TLR2-Mediated Innate Immunity

mBio ◽  
2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Nihal A. Okan ◽  
Sabina Chalabaev ◽  
Tae-Hyun Kim ◽  
Avner Fink ◽  
Robin A. Ross ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Innate Immune Response ◽  
Francisella Tularensis ◽  
Innate Immune ◽  
Content Type ◽  
Tnf Α ◽  
Schu S4 ◽  
Highly Virulent

ABSTRACT The highly virulent Francisella tularensis subsp. tularensis has been classified as a category A bioterrorism agent. A live vaccine strain (LVS) has been developed but remains unlicensed in the United States because of an incomplete understanding of its attenuation. Lipopolysaccharide (LPS) modification is a common strategy employed by bacterial pathogens to avoid innate immunity. A novel modification enzyme has recently been identified in F. tularensis and Helicobacter pylori. This enzyme, a two-component Kdo (3-deoxy-d-manno-octulosonic acid) hydrolase, catalyzes the removal of a side chain Kdo sugar from LPS precursors. The biological significance of this modification has not yet been studied. To address the role of the two-component Kdo hydrolase KdhAB in F. tularensis pathogenesis, a ΔkdhAB deletion mutant was constructed from the LVS strain. In intranasal infection of mice, the ΔkdhAB mutant strain had a 50% lethal dose (LD50) 2 log10 units higher than that of the parental LVS strain. The levels of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) in bronchoalveolar lavage fluid were significantly higher (2-fold) in mice infected with the ΔkdhAB mutant than in mice infected with LVS. In vitro stimulation of bone marrow-derived macrophages with the ΔkdhAB mutant induced higher levels of TNF-α and IL-1β in a TLR2-dependent manner. In addition, TLR2−/− mice were more susceptible than wild-type mice to ΔkdhAB bacterial infection. Finally, immunization of mice with ΔkdhAB bacteria elicited a high level of protection against the highly virulent F. tularensis subsp. tularensis strain Schu S4. These findings suggest an important role for the Francisella Kdo hydrolase system in virulence and offer a novel mutant as a candidate vaccine. IMPORTANCE The first line of defense against a bacterial pathogen is innate immunity, which slows the progress of infection and allows time for adaptive immunity to develop. Some bacterial pathogens, such as Francisella tularensis, suppress the early innate immune response, killing the host before adaptive immunity can mature. To avoid an innate immune response, F. tularensis enzymatically modifies its lipopolysaccharide (LPS). A novel LPS modification—Kdo (3-deoxy-d-manno-octulosonic acid) saccharide removal—has recently been reported in F. tularensis. We found that the ∆kdhAB mutant was significantly attenuated in mice. Additionally, the mutant strain induced an early innate immune response in mice both in vitro and in vivo. Immunization of mice with this mutant provided protection against the highly virulent F. tularensis strain Schu S4. Thus, our study has identified a novel LPS modification important for microbial virulence. A mutant lacking this modification may be used as a live attenuated vaccine against tularemia.

scholarly journals MYCOBACTERIUM TUBERCULOSIS SISTEM IMUN ALAMIAH TERKAIT PENERIMANYA

2016 ◽  
Vol 19 (1) ◽  
pp. 45
Author(s):  
Jusak Nugraha
Keyword(s):  
Immune Response ◽  
Inflammatory Cytokine ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
Myeloid Differentiation ◽  
Toll Like Receptor ◽  
Protective Function ◽  
Adaptive Immune ◽  
Tnf Α ◽  
Myeloid Differentiation Factor

Various attemp to investigate immune response towards tuberculosis has been done in order to eradicate or to make vaccination against tuberculosis (TB) effectively. Recently it is known that innate immunity has an important role in immunity to TB despite adaptive immune response, because it was proved that adaptive immune response alone was not sufficient to eradicate this microorganism thoroughly and completely in patient’s body. After Toll-Like Receptor (TLR) was found in the end of the 20th century, many progresses has been obtained in understanding about the activation of this innate immune response. But it is still needed to understand more deeply in the immune response to M. tuberculosis to lead the development of therapy or vaccination that bring into more precise target. The activation through TLR by parts of Mycobacterium induce cytoplasm protein adaptor MyD88 (Myeloid Differentiation factor 88). MyD88 has the function to activate NF- κB and secrete pro-inflammatory cytokine such as TNF-α, IL-6, IL-12. Involvement of MyD88 is not solely dependent of TLR2 receptor and there are another pathways to induce protective function of immunocompetent cells in TB.

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