scholarly journals Bacterium-Dependent Induction of Cytokines in Mononuclear Cells and Their Pathologic Consequences In Vivo

1999 ◽  
Vol 67 (5) ◽  
pp. 2125-2130 ◽  
Author(s):  
Yanling Jiang ◽  
Luciano Magli ◽  
Michael Russo
Keyword(s):  
Inflammatory Response ◽  
Mononuclear Cells ◽  
Oral Bacteria ◽  
Interleukin 12 ◽  
Potent Inducer ◽  
Tnf Α ◽  
Oral Pathogens ◽  
Ifn Γ

ABSTRACT Viridans streptococci are a heterogeneous group of gram-positive bacteria that are normal inhabitants of the mouth. These organisms are thought to contribute significantly to the etiology of infective endocarditis, although recently they have been implicated in serious infections in other settings. Another group of oral bacteria, gram-negative anaerobes, is associated with chronic dental infections, such as periodontal diseases or endodontic lesion formation. We evaluated the ability of the oral pathogens Streptococcus mutans and Porphyromonas endodontalis to induce a pathogenic response in vivo, with the goal of quantifying the inflammatory response in soft tissue by measuring leukocyte recruitment and hard tissues by measuring osteoclastogenesis. S. mutansinduced a strong inflammatory response and was a potent inducer of osteoclast formation, while P. endodontalis was not. To further study the mechanisms by which P. endodontalis andS. mutans elicit significantly different levels of inflammatory responses in vivo, we tested the capacity of each to induce production of cytokines by mononuclear cells in vitro. S. mutans stimulated high levels of interleukin-12 (IL-12), gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α), all of which are associated with inflammation, enhanced monocyte function, and generation of a Th1 response. In contrast, P. endodontalisstimulated production of IL-10 but not of TNF-α, IL-12, or IFN-γ. These results demonstrate that oral pathogens differ dramatically in their abilities to induce inflammatory and immunoregulatory cytokines. Moreover, there is a high degree of correlation between the cytokine profile induced by these bacteria in vitro and their pathogenic capacity in vivo.

scholarly journals Acquisition of Hemozoin by Monocytes Down-Regulates Interleukin-12 p40 (IL-12p40) Transcripts and Circulating IL-12p70 through an IL-10-Dependent Mechanism: In Vivo and In Vitro Findings in Severe Malarial Anemia

2006 ◽  
Vol 74 (9) ◽  
pp. 5249-5260 ◽  
Author(s):  
Christopher C. Keller ◽  
Ouma Yamo ◽  
Collins Ouma ◽  
John Michael Ong'echa ◽  
David Ounah ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Mononuclear Cells ◽  
Interleukin 12 ◽  
Peripheral Blood Mononuclear ◽  
Necrosis Factor Alpha ◽  
Severe Malarial Anemia ◽  
Tnf Α ◽  
Malarial Anemia

ABSTRACT Severe malarial anemia (SMA) is a primary cause of morbidity and mortality in immune-naïve infants and young children residing in areas of holoendemic Plasmodium falciparum transmission. Although the immunopathogenesis of SMA is largely undefined, we have previously shown that systemic interleukin-12 (IL-12) production is suppressed during childhood blood-stage malaria. Since IL-10 and tumor necrosis factor alpha (TNF-α) are known to decrease IL-12 synthesis in a number of infectious diseases, altered transcriptional regulation of these inflammatory mediators was investigated as a potential mechanism for IL-12 down-regulation. Ingestion of naturally acquired malarial pigment (hemozoin [PfHz]) by monocytes promoted the overproduction of IL-10 and TNF-α relative to the production of IL-12, which correlated with an enhanced severity of malarial anemia. Experiments with cultured peripheral blood mononuclear cells (PBMC) and CD14+ cells from malaria-naïve donors revealed that physiological concentrations of PfHz suppressed IL-12 and augmented IL-10 and TNF-α by altering the transcriptional kinetics of IL-12p40, IL-10, and TNF-α, respectively. IL-10 neutralizing antibodies, but not TNF-α antibodies, restored PfHz-induced suppression of IL-12. Blockade of IL-10 and the addition of recombinant IL-10 to cultured PBMC from children with SMA confirmed that IL-10 was responsible for malaria-induced suppression of IL-12. Taken together, these results demonstrate that PfHz-induced up-regulation of IL-10 is responsible for the suppression of IL-12 during malaria.

scholarly journals A ComparativeIn VitroStudy of the Effects of Separate and Combined Products ofCitrus e fructibusandCydonia e fructibuson Immunological Parameters of Seasonal Allergic Rhinitis

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
E. W. Baars ◽  
M. C. Jong ◽  
I. Boers ◽  
A. F. M. Nierop ◽  
H. F. J. Savelkoul
Keyword(s):  
Allergic Rhinitis ◽  
Seasonal Allergic Rhinitis ◽  
Mononuclear Cells ◽  
Immunological Parameters ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α ◽  
Ifn Γ ◽  
Specific Stimulation

This paper examined the effects of the combined product,Citrus e fructibus/Cydonia e fructibus(Citrus/Cydonia; Citrus and Cydonia: each 0.01 g/mL), and separate products of Citrus (0.01 g/mL) and Cydonia (0.01 g/mL) on the immunological pathways involved in seasonal allergic rhinitis (SAR). Peripheral blood mononuclear cells (PBMCs) from five healthy and five grass pollen-allergic donors were isolated and analyzedin vitroafter polyclonal and allergen-specific stimulation of T cells in the presence of the three extracts. The analyses demonstrated acceptable cell survival with no signs of toxicity. Citrus mainly had a selective effect on reducing allergen-specific chronic inflammatory (TNF-α; Citrus compared to Cydonia and Citrus/Cydonia: −87.4 (P<0.001) and −68.0 (P<0.05), resp.) and Th2 pathway activity (IL-5; Citrus compared to Cydonia: −217.8 (P<0.01); while, both Cydonia and Citrus/Cydonia mainly affected the induction of the allergen-specific Th1 pathway (IFN-γ; Cydonia and Citrus/Cydonia compared to Citrus: 3.8 (P<0.01) and 3.0 (P<0.01), resp.). Citrus and Cydonia demonstrated different working mechanisms in the treatment of SAR and the combination product did not demonstrate larger effects than the separate preparations. Further effectiveness and efficacy studies comparing the effects of the products on SARin vivoare indicated.

scholarly journals Pentoxifylline Inhibits Superantigen-Induced Toxic Shock and Cytokine Release

1999 ◽  
Vol 6 (4) ◽  
pp. 594-598 ◽  
Author(s):  
Teresa Krakauer ◽  
Bradley G. Stiles
Keyword(s):  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Toxic Shock ◽  
Peripheral Blood Mononuclear ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Ifn Γ ◽  
Toxic Shock Syndrome Toxin

ABSTRACT Tumor necrosis factor alpha (TNF-α) is a critical cytokine that mediates the toxic effects of bacterial superantigens like staphylococcal enterotoxin B (SEB) and toxic shock syndrome toxin 1 (TSST-1). Pentoxifylline, an anti-inflammatory agent that inhibits endotoxemia and lipopolysaccharide (LPS)-induced release of TNF-α, was tested for its ability to inhibit SEB- and TSST-1-induced activation of human peripheral blood mononuclear cells (PBMCs) in vitro and toxin-mediated shock in mice. Stimulation of PBMCs by SEB or TSST-1 was effectively blocked by pentoxifylline (10 mM), as evidenced by the inhibition of TNF-α, interleukin 1β (IL-1β), gamma interferon (IFN-γ), and T-cell proliferation. The levels of TNF-α, IL-1α, and IFN-γ in serum after an SEB or TSST-1 injection were significantly lower in mice given pentoxifylline (5.5 mg/animal) versus control mice. Additionally, pentoxifylline diminished the lethal effects and temperature fluctuations elicited by SEB and TSST-1. Thus, in addition to treating endotoxemias, the cumulative in vitro and in vivo data suggest that pentoxifylline may also be useful in abrogating the ill effects of staphylococcal enterotoxins and TSST-1.

scholarly journals Nramp1 Is Not a Major Determinant in the Control of Brucella melitensis Infection in Mice

2003 ◽  
Vol 71 (2) ◽  
pp. 621-628 ◽  
Author(s):  
Laurence A. Guilloteau ◽  
Jacques Dornand ◽  
Antoine Gross ◽  
Michel Olivier ◽  
Fabienne Cortade ◽  
...  
Keyword(s):  
Brucella Melitensis ◽  
Natural Resistance ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Reverse Transcription Pcr ◽  
Tnf Α ◽  
Ifn Γ ◽  
Oxide Synthase

ABSTRACT Brucella, the causative agent of brucellosis in animals and humans, can survive and proliferate within macrophages. Macrophages mediate mouse resistance to various pathogens through the expression of the Nramp1 gene. The role of this gene in the control of Brucella infection was investigated. When BALB/c mice (Nramp1s ) and C.CB congenic mice (Nramp1r ) were infected with Brucella melitensis, the number of Brucella organisms per spleen was significantly larger in the C.CB mice than in the BALB/c mice during the first week postinfection (p.i.). This Nramp1-linked susceptibility to Brucella was temporary, since similar numbers of Brucella were recovered from the two strains of mice 2 weeks p.i. The effect of Nramp1 expression occurred within splenocytes intracellularly infected by Brucella. However, there was no difference between in vitro replication rates of Brucella in macrophages isolated from the two strains of mice infected in vivo or in Nramp1 RAW264 transfectants. In mice, infection with Brucella induced an inflammatory response, resulting in splenomegaly and recruitment of phagocytes in the spleen, which was amplified in C.CB mice. Reverse transcription-PCR (RT-PCR), performed 5 days p.i., showed that inducible nitric oxide synthase, tumor necrosis factor alpha (TNF-α), interleukin-12 p40 (IL-12p40), gamma interferon (IFN-γ), and IL-10 mRNAs were similarly induced in spleens of the two strains. In contrast, the mRNA of KC, a C-X-C chemokine, was induced only in infected C.CB mice at this time. This pattern of mRNA expression was maintained at 14 days p.i., with IFN-γ and IL-12p40 mRNAs being more intensively induced in the infected C.CB mice, but TNF-α mRNA was no longer induced. The higher recruitment of neutrophils observed in the spleens of infected C.CB mice could explain the temporary susceptibility of C.CB mice to B. melitensis infection. In contrast to infections with Salmonella, Leishmania, and Mycobacterium, the expression of the Nramp1 gene appears to be of limited importance for the natural resistance of mice to Brucella.

scholarly journals Analysis of Porcine Pro- and Anti-Inflammatory Cytokine Induction by S. suis In Vivo and In Vitro

Pathogens ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 40 ◽  
Author(s):  
Florian S. Hohnstein ◽  
Marita Meurer ◽  
Nicole de Buhr ◽  
Maren von Köckritz-Blickwede ◽  
Christoph G. Baums ◽  
...  
Keyword(s):  
Whole Blood ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Bacterial Killing ◽  
Tnf Α ◽  
Specific Igg ◽  
Ifn Γ ◽  
Weaning Piglets

Weaning piglets are susceptible to the invasive Streptococcus (S.) suis infection, which can result in septicemia. The aim of this study was to investigate the cytokine profile induced upon S. suis infection of blood, to determine the cellular sources of those cytokines, and to study the potential effects of the induced cytokines on bacterial killing. We measured TNF-α, IL-6, IFN-γ, IL-17A and IL-10 after an experimental intravenous infection with S. suis serotype 2 in vivo, and analyzed whole blood, peripheral blood mononuclear cells (PBMC) and separated leukocytes to identify the cytokine-producing cell type(s). In addition, we used a reconstituted whole blood assay to investigate the effect of TNF-α on bacterial killing in the presence of different S. suis-specific IgG levels. An increase in IL-6 and IL-10, but not in IFN-γ or IL-17A, was observed in two of three piglets with pronounced bacteremia 16 to 20 h after infection, but not in piglets with controlled bacteremia. Our results confirmed previous findings that S. suis induces TNF-α and IL-6 and could demonstrate that TNF-α is produced by monocytes in vitro. We further found that IL-10 induction resulted in reduced secretion of TNF-α and IL-6. Rapid induction of TNF-α was, however, not crucial for in vitro bacterial killing, not even in the absence of specific IgG.

scholarly journals CD40 Ligation Prevents Trypanosoma cruziInfection through Interleukin-12 Upregulation

1999 ◽  
Vol 67 (4) ◽  
pp. 1929-1934 ◽  
Author(s):  
Damien Chaussabel ◽  
Frédérique Jacobs ◽  
Jan de Jonge ◽  
Marijke de Veerman ◽  
Yves Carlier ◽  
...  
Keyword(s):  
De Novo ◽  
Critical Role ◽  
Interleukin 12 ◽  
No Production ◽  
Cd40 Ligation ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT Because of the critical role of the CD40-CD40 ligand (CD40L) pathway in the induction and effector phases of immune responses, we investigated the effects of CD40 ligation on the control ofTrypanosoma cruzi infection. First, we observed that supernatants of murine spleen cells stimulated by CD40L-transfected 3T3 fibroblasts (3T3-CD40L transfectants) prevent the infection of mouse peritoneal macrophages (MPM) by T. cruzi. This phenomenon depends on de novo production of nitric oxide (NO) as it is prevented by the addition of N-nitro-l-arginine methyl ester, a NO synthase inhibitor. NO production requires interleukin (IL)-12-mediated gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) synthesis as demonstrated by inhibition experiments using neutralizing anti-IL-12, anti-IFN-γ, and anti-TNF-α monoclonal antibodies (MAb). We found that an activating anti-CD40 MAb also directly stimulates IFN-γ-activated MPM to produce NO and thereby to control T. cruzi infection. To determine the in vivo relevance of these in vitro findings, mice were injected with 3T3-CD40L transfectants or 3T3 control fibroblasts at the time ofT. cruzi inoculation. We observed that in vivo CD40 ligation dramatically reduced both parasitemia and the mortality rate of T. cruzi-infected mice. A reduced parasitemia was still observed when the injection of 3T3-CD40L transfectants was delayed 8 days postinfection. It was abolished by injection of anti-IL-12 MAb. Taken together, these data establish that CD40 ligation facilitates the control of T. cruzi infection through a cascade involving IL-12, IFN-γ, and NO.

scholarly journals Protein A Modulates Neutrophil and Keratinocyte Signaling and Survival in Response to Staphylococcus aureus

2021 ◽  
Vol 11 ◽  
Author(s):  
Camila Ledo ◽  
Cintia D. Gonzalez ◽  
Ailin Garofalo ◽  
Florencia Sabbione ◽  
Irene A. Keitelman ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Death ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Protein A ◽  
Human Neutrophils ◽  
Potent Inducer ◽  
Tnf Α

The type 1 TNF-α receptor (TNFR1) has a central role in initiating both pro-inflammatory and pro-apoptotic signaling cascades in neutrophils. Considering that TNFR1 signals Staphylococcus aureus protein A (SpA), the aim of this study was to explore the interaction of this bacterial surface protein with neutrophils and keratinocytes to underscore the signaling pathways that may determine the fate of these innate immune cells in the infected tissue during staphylococcal skin infections. Using human neutrophils cultured in vitro and isogenic staphylococcal strains expressing or not protein A, we demonstrated that SpA is a potent inducer of IL-8 in neutrophils and that the induction of this chemokine is dependent on the SpA-TNFR1 interaction and p38 activation. In addition to IL-8, protein A induced the expression of TNF-α and MIP-1α highlighting the importance of SpA in the amplification of the inflammatory response. Protein A contributed to reduce neutrophil mortality prolonging their lifespan upon the encounter with S. aureus. Signaling initiated by SpA modulated the type of neutrophil cell death in vitro and during skin and soft tissue infections (SSTI) in vivo triggering the apoptotic pathway instead of necrosis. Moreover, SpA induced pro-inflammatory cytokines in keratinocytes, modulating their survival in vitro and preventing the exacerbated necrosis and ulceration of the epithelium during SSTI in vivo. Taken together, these results highlight the importance of the inflammatory signaling induced by protein A in neutrophils and skin epithelial cells. The ability of protein A to modulate the neutrophil/epithelial cell death program in the skin is of clinical relevance considering that lysis of neutrophils and epithelial cells will promote an intense inflammatory response and contribute to tissue damage, a non-desirable feature of complicated SSTI.

scholarly journals Regulation of Interleukin-12 by Complement Receptor 3 Signaling

1997 ◽  
Vol 185 (11) ◽  
pp. 1987-1995 ◽  
Author(s):  
Thomas Marth ◽  
Brian L. Kelsall
Keyword(s):  
Mononuclear Cells ◽  
Histoplasma Capsulatum ◽  
Human Peripheral Blood ◽  
Interleukin 12 ◽  
Cell Mediated Immunity ◽  
Complement Receptor ◽  
Peripheral Blood Mononuclear ◽  
Ifn Γ

Complement receptor type 3 (CR3, CD11b/CD18) serves as a receptor for a number of endogenous ligands and infectious organisms, and is involved in adhesion and host defense functions. Here, we report that signaling via CR3 plays an important role in regulating production of interleukin-12 (IL-12), a key mediator of cell-mediated immunity (CMI). We demonstrate with a variety of stimuli a dose-dependent, specific downregulation of IL-12 secretion by human monocytes in vitro after exposure to antibodies to CR3 (anti-CD11b and anti-CD18), as well as to the natural CR3 ligands, iC3b, and Histoplasma capsulatum. CR3 antibodies also suppressed interferon-γ (IFN-γ) production in cultures of human peripheral blood mononuclear cells (PBMC). We determined that one mechanism by which CR3 antibodies may suppress IL-12 production is by the inhibition of IFN-γ–induced tyrosine phosphorylation. Finally, in a murine model of IL-12–dependent septic shock, we provide evidence that administration of CR3 antibodies leads to suppression of IL-12 and IFN-γ in vivo. Our studies thus define a novel role for CR3 in regulating CMI functions via IL-12.

scholarly journals Local Immune Responses to Chlamydia pneumoniae in the Lungs of BALB/c Mice during Primary Infection and Reinfection

1998 ◽  
Vol 66 (11) ◽  
pp. 5113-5118 ◽  
Author(s):  
Jenni M. Penttilä ◽  
Marjukka Anttila ◽  
Mirja Puolakkainen ◽  
Aino Laurila ◽  
Kari Varkila ◽  
...  
Keyword(s):  
Primary Infection ◽  
Bacterial Infections ◽  
Chlamydia Pneumoniae ◽  
Mononuclear Cells ◽  
Relative Increase ◽  
Culturable Bacteria ◽  
Ifn Γ ◽  
Tissue Reactions

ABSTRACT Cell-mediated immune (CMI) responses play a major role in protection as well as pathogenesis of many intracellular bacterial infections. In this study, we evaluated the infection kinetics and assessed histologically the lymphoid reactions and local, in vitro-restimulated CMI responses in lungs of BALB/c mice, during both primary infection and reinfection with Chlamydia pneumoniae. The primary challenge resulted in a self-restricted infection with elimination of culturable bacteria by day 27 after challenge. A mild lymphoid reaction characterized the pathology in the lungs. In vitro CMI responses consisted of a weak proliferative response and no secretion of gamma interferon (IFN-γ). The number of lung-derived mononuclear cells increased substantially during the primary infection; the largest relative increase was observed in B cells (B220+). After reinfection, the number of lung-derived mononuclear cells increased further, and the response consisted mainly of T cells. The reinfection was characterized in vivo by significant protection from infection (fewer cultivable bacteria in the lungs for a shorter period of time) but increased local lymphoid reaction at the infection site. In vitro, as opposed to the response in naive mice, acquired immunity was characterized by a strongly Th1-biased (IFN-γ) CMI response. These results suggest that repeated infections with C. pneumoniae may induce Th1-type responses with similar associated tissue reactions, as shown in C. trachomatis infection models.

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