scholarly journals Oral P. gingivalis impairs gut permeability and mediates immune responses associated with neurodegeneration in LRRK2 R1441G mice

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Yu-Kun Feng ◽  
Qiong-Li Wu ◽  
Yan-Wen Peng ◽  
Feng-Yin Liang ◽  
Hua-Jing You ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Chronic Periodontitis ◽  
Mononuclear Cells ◽  
Late Onset ◽  
Peripheral Inflammation ◽  
Interleukin 17A ◽  
Tnf Α ◽  
Lrrk2 Gene ◽  
Necrosis Factor

Abstract Background The R1441G mutation in the leucine-rich repeat kinase 2 (LRRK2) gene results in late-onset Parkinson’s disease (PD). Peripheral inflammation and gut microbiota are closely associated with the pathogenesis of PD. Chronic periodontitis is a common type of peripheral inflammation, which is associated with PD. Porphyromonas gingivalis (Pg), the most common bacterium causing chronic periodontitis, can cause alteration of gut microbiota. It is not known whether Pg-induced dysbiosis plays a role in the pathophysiology of PD. Methods In this study, live Pg were orally administrated to animals, three times a week for 1 month. Pg-derived lipopolysaccharide (LPS) was used to stimulate mononuclear cells in vitro. The effects of oral Pg administration on the gut and brain were evaluated through behaviors, morphology, and cytokine expression. Results Dopaminergic neurons in the substantia nigra were reduced, and activated microglial cells were increased in R1441G mice given oral Pg. In addition, an increase in mRNA expression of tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) as well as protein level of α-synuclein together with a decrease in zonula occludens-1 (Zo-1) was detected in the colon in Pg-treated R1441G mice. Furthermore, serum interleukin-17A (IL-17A) and brain IL-17 receptor A (IL-17RA) were increased in Pg-treated R1441G mice. Conclusions These findings suggest that oral Pg-induced inflammation may play an important role in the pathophysiology of LRRK2-associated PD.

scholarly journals Chronic oral administration of P. gingivalis induces microglial activation and degeneration of dopaminergic neurons possibly through increase in gut permeability and peripheral IL-17A in LRRK2 R1441G mice

2020 ◽  
Author(s):  
Yu-kun Feng ◽  
Yan-Wen Peng ◽  
Qiong-Li Wu ◽  
Feng-Yin Liang ◽  
Hua-Jing You ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Chronic Periodontitis ◽  
Dopaminergic Neurons ◽  
Microglial Activation ◽  
Mononuclear Cells ◽  
Late Onset ◽  
Interleukin 1 ◽  
Peripheral Inflammation ◽  
Peripheral Blood Mononuclear

Abstract Background The R1441G mutation in the leucine-rich repeat kinase 2 (LRRK2) gene results in late-onset Parkinson’s disease (PD). Peripheral inflammation and gut microbiota are closely associated with the pathogenesis of PD. Chronic periodontitis is a common type of peripheral inflammation, which is associated with PD. Porphyromonas gingivalis (Pg), the most common bacterium causing chronic periodontitis, can cause alteration of gut microbiota. It is not known whether Pg-induced dysbiosis plays a role in the pathophysiology of PD. Methods In this study, live Pg were orally administrated to animals, three times a week for one month. Pg-derived lipopolysaccharide (LPS) was used to stimulate peripheral blood mononuclear cells in vitro. The effects of oral Pg administration on the gut and brain were evaluated through behaviors, morphology, and cytokine expression. Results Dopaminergic neurons in the substantia nigra were reduced and activated microglial cells were increased in R1441G mice given oral Pg. In addition, an increase in mRNA expression of tumor necrosis factor (TNF-α) and interleukin-1 β (IL-1β) as well as protein level of α-synuclein together with a decrease in zonula occludens-1 (Zo-1) were detected in the colon in Pg-treated R1441G mice. Furthermore, serum interleukin-17A (IL-17A) and brain IL-17 receptor A (IL-17RA) were increased in Pg-treated R1441G mice. Conclusions These findings suggest that LRRK2 causes gut leakage and further mediates peripheral IL-17A response in Pg-treated animals. We, thus, put forward the hypothesis that IL-17A in the serum may result in activation of the IL-17A-IL-17RA axis that aggravates dysfunction of dopaminergic neurons and provokes microglial activation in LRRK2 R1441G mice.

scholarly journals Diagnostic Implications of Antigen-Induced Gamma Interferon, Nitric Oxide, and Tumor Necrosis Factor Alpha Production by Peripheral Blood Mononuclear Cells from Mycobacterium bovis-Infected Cattle

2003 ◽  
Vol 10 (5) ◽  
pp. 960-966 ◽  
Author(s):  
W. R. Waters ◽  
M. V. Palmer ◽  
D. L. Whipple ◽  
M. P. Carlson ◽  
B. J. Nonnecke
Keyword(s):  
Bovine Tuberculosis ◽  
Tumor Necrosis ◽  
Mononuclear Cells ◽  
Infected Cattle ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Necrosis Factor

ABSTRACT Bovine tuberculosis in the United States has proven costly to cattle producers as well as to government regulatory agencies. While in vivo responsiveness to mycobacterial antigens is the current standard for the diagnosis of tuberculosis, in vitro assays are gaining acceptance, especially as ancillary or complementary tests. To evaluate in vitro indices of cellular sensitization, antigen-induced gamma interferon (IFN-γ), nitric oxide (NO), and tumor necrosis factor alpha (TNF-α) responses by blood mononuclear cells from Mycobacterium bovis-infected cattle were quantified and compared. Using an aerosol model of infection, two doses of each of two strains of M. bovis (95-1315 and HC-2045T) were used to induce a range of IFN-γ, NO, and TNF-α responses. Infection-specific increases in NO, but not in IFN-γ or TNF-α, were detected in nonstimulated cultures at 48 h, a finding that is indicative of nonspecific activation and spontaneous release of NO. The infective dose of M. bovis organisms also influenced responses. At 34 days postinfection, IFN-γ, NO, and TNF-α responses in antigen-stimulated cells from cattle receiving 105 CFU of M. bovis organisms were greater than responses of cells from cattle infected with 103 CFU of M. bovis organisms. The NO response, but not the IFN-γ and TNF-α responses, was influenced by infective strains of M. bovis. The TNF-α, NO, and IFN-γ responses followed similar kinetics, with strong positive associations among the three readouts. Overall, these findings indicate that NO and TNF-α, like IFN-γ, may prove useful as indices for the diagnosis of bovine tuberculosis.

Production of tumour necrosis factor by cells exposed to sulphonamide reactive metabolites

1992 ◽  
Vol 70 (5) ◽  
pp. 719-722 ◽  
Author(s):  
Michael J. Rieder ◽  
Monica Mask ◽  
Ingrid A. Bird
Keyword(s):  
Inflammatory Response ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Mononuclear Cells ◽  
Reactive Metabolites ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α ◽  
Presence And Absence ◽  
Necrosis Factor

Hypersensitivity reactions are the most common adverse events associated with therapy with the sulphonamide antibiotics. These reactions have been shown to occur among individuals with pharmacogenetically determined differences in the capacity of their cells to detoxify reactive products of oxidative metabolism of the sulphonamides. These reactions appear to be propagated by an inflammatory response by the immune system. To investigate the role of the cytokine tumour necrosis factor (TNF-α) in these reactions, we studied the production of TNF-α by peripheral blood mononuclear cells (PBMCs) that had been incubated with sulfamethoxazole and murine microsomes in the presence and absence of a microsomal-activating system and TNF-α production by PBMCs in the presence and absence of the hydroxylamine derivative of sulfamethoxazole. The PBMCs showed a time-related increase in the production of TNF-α. There was no increase in TNF-α production seen during incubation with sulphonamide reactive metabolites; rather, there was a decrease in TNF-α elaboration that was most marked when PBMCs were incubated with the hydroxylamine of sulfamethoxazole. There is no evidence from these in vitro studies that TNF-α is involved as a mediator of the inflammatory response in sulphonamide hypersensitivity adverse drug reactions.Key words: sulphonamide, tumour necrosis factor, adverse drug reaction, hydroxylamine.

scholarly journals Effect of a Histone Deacetylases Inhibitor of IL-18 and TNF-Alpha Secretion in Vitro

2018 ◽  
Vol 6 (2) ◽  
pp. 269-273
Author(s):  
Zlatka Georgieva Dobreva ◽  
Boncho Grigorov Grigorov ◽  
Spaska Angelova Stanilova
Keyword(s):  
Gene Expression ◽  
Histone Deacetylases ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor ◽  
Inactive Protein

BACKGROUND: Interleukin-18 (IL-18) and Tumor Necrosis Factor-alpha (TNF-α) are proinflammatory cytokines that increased the development of Th1 immune response, but have a different type of regulation of the gene expression. Whereas TNF-α has an inducible expression, IL-18 is translated as an inactive protein and required proteolytic cleavage by Casp-1 in inflammasome complexes.AIM: To investigate the effect of the histone deacetylases inhibitor Suberoylanilide Hydroxamic Acid (SAHA) on the gene expression and secretion of both cytokines, IL-18 and TNF-α, according to their contribution to the cancer development and anticancer immunity.METHODS: Isolated peripheral blood mononuclear cells (PBMC) were stimulated with LPS and C3bgp with or without SAHA. Cytokine production was assessed by ELISA at 6 and 24h.RESULTS: IL-18 and TNF-α secretion was significantly increased at 6h and 24h in response to stimulation. TNF-α production from stimulated PBMC was downregulated by SAHA at 6 and 24h. Treatment with SAHA does not inhibit the secretion of IL-18 significantly either at 6 or 24h of stimulation.CONCLUSION: The inhibition of histone deacetylases by SAHA does not influence the inflammasome-dependent production of immunologically active IL-18. In contrast, the production of proinflammatory TNF-α in cultures was mediated by the activity of HDAC class I and class II enzymes.

scholarly journals Immunoglobulin A1 Protease, an Exoenzyme of Pathogenic Neisseriae, Is a Potent Inducer of Proinflammatory Cytokines

1999 ◽  
Vol 190 (8) ◽  
pp. 1049-1058 ◽  
Author(s):  
Dirk R. Lorenzen ◽  
Frank Düx ◽  
Uwe Wölk ◽  
Anastasios Tsirpouchtsidis ◽  
Gaby Haas ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Mononuclear Cells ◽  
Native Form ◽  
Peripheral Blood Mononuclear ◽  
Potent Inducer ◽  
Cytokine Induction ◽  
Regulatory Cytokine ◽  
Iga1 Protease ◽  
Tnf Α ◽  
Necrosis Factor

A characteristic of human pathogenic Neisseriae is the production and secretion of an immunoglobulin (Ig)A1-specific serine protease (IgA1 protease) that cleaves preferentially human IgA1 and other target proteins. Here we show a novel function for native IgA1 protease, i.e., the induction of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 from peripheral blood mononuclear cells. The capacity of IgA1 protease to elicit such cytokine responses in monocytes was enhanced in the presence of T lymphocytes. IgA1 protease did not induce the regulatory cytokine IL-10, which was, however, found in response to lipopolysaccharide and phytohemagglutinin. The immunomodulatory effects caused by IgA1 protease require a native form of the enzyme, and denaturation abolished cytokine induction. However, the proteolytic activity is not required for the cytokine induction by IgA1 protease. Our results indicate that IgA1 protease exhibits important immunostimulatory properties and may contribute substantially to the pathogenesis of neisserial infections by inducing large amounts of TNF-α and other proinflammatory cytokines. In particular, IgA1 protease may represent a key virulence determinant of bacterial meningitis.

Epinephrine inhibits endotoxin-induced IL-1β production: roles of tumor necrosis factor-α and IL-10

1997 ◽  
Vol 273 (6) ◽  
pp. R1885-R1890 ◽  
Author(s):  
Tom Van Der Poll ◽  
Stephen F. Lowry
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Ex Vivo ◽  
Systemic Infection ◽  
Tnf Α ◽  
Cytokine Tumor Necrosis Factor ◽  
Dose Dependent Decrease ◽  
Factor Α ◽  
Necrosis Factor

Epinephrine has been found to inhibit the production of the proinflammatory cytokine tumor necrosis factor (TNF)-α and to enhance the production of anti-inflammatory cytokine interleukin (IL)-10. To determine the effect of epinephrine on IL-1β production, the following experiments were performed: 1) blood obtained from subjects at 4–21 h after the start of a continuous infusion of epinephrine (30 ng ⋅ kg−1⋅ min−1) produced less IL-1β after ex vivo stimulation with lipopolysaccharide (LPS), compared with blood drawn from subjects infused with saline; 2) in whole blood in vitro, epinephrine caused a dose-dependent decrease in LPS-induced IL-1β production, which was likely mediated via adrenergic receptors; and 3) inhibition of TNF and enhancement of IL-10 both contributed to epinephrine-induced inhibition of IL-1β production. Epinephrine, either endogenously produced or administered as a component of sepsis treatment, may attenuate excessive activity of proinflammatory cytokines early in the course of systemic infection.

scholarly journals Ectopic HOXB4 overcomes the inhibitory effect of tumor necrosis factor-α on Fanconi anemia hematopoietic stem and progenitor cells

Blood ◽  
2009 ◽  
Vol 113 (21) ◽  
pp. 5111-5120 ◽  
Author(s):  
Michael D. Milsom ◽  
Bernhard Schiedlmeier ◽  
Jeff Bailey ◽  
Mi-Ok Kim ◽  
Dandan Li ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Fanconi Anemia ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Ectopic Expression ◽  
Hematopoietic Stem ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

AbstractEctopic delivery of HOXB4 elicits the expansion of engrafting hematopoietic stem cells (HSCs). We hypothesized that inhibition of tumor necrosis factor-α (TNF-α) signaling may be central to the self-renewal signature of HOXB4. Because HSCs derived from Fanconi anemia (FA) knockout mice are hypersensitive to TNF-α, we studied Fancc−/− HSCs to determine the physiologic effects of HOXB4 on TNF-α sensitivity and the relationship of these effects to the engraftment defect of FA HSCs. Overexpression of HOXB4 reversed the in vitro hypersensitivity to TNF-α of Fancc−/− HSCs and progenitors (P) and partially rescued the engraftment defect of these cells. Coexpression of HOXB4 and the correcting FA-C protein resulted in full correction compared with wild-type (WT) HSCs. Ectopic expression of HOXB4 resulted in a reduction in both apoptosis and reactive oxygen species in Fancc−/− but not WT HSC/P. HOXB4 overexpression was also associated with a significant reduction in surface expression of TNF-α receptors on Fancc−/− HSC/P. Finally, enhanced engraftment was seen even when HOXB4 was expressed in a time-limited fashion during in vivo reconstitution. Thus, the HOXB4 engraftment signature may be related to its effects on TNF-α signaling, and this pathway may be a molecular target for timed pharmacologic manipulation of HSC during reconstitution.

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