Endogenous and Exogenous Glucocorticoids in Experimental Enterococcal Infection

ABSTRACT The potentially protective role of the host adrenal-glucocorticoid response to enterococcal infection was evaluated in an experimental model in which mice were infected intraperitoneally with two distinct Enterococcus faecalis strains (K9 and CP-1). We demonstrated that corticosterone levels in serum and peritoneal-lavage fluid were elevated within 1 hour of infection with either E. faecalis strain. We also demonstrated that adrenalectomized mice generated a more robust localized peritoneal tumor necrosis factor alpha (TNF-α) response to both E. faecalis strains than did sham-adrenalectomized mice but that neither E. faecalis strain induced a systemic TNF-α response. Further, peritoneal TNF-α production in adrenalectomized mice infected with either E. faecalis K9 or CP-1 was suppressed by prior treatment with an exogenous glucocorticoid (dexamethasone). The potential clinical significance of these results was suggested by our findings that adrenalectomy markedly increased susceptibility (a >100-fold decrease in the 50% lethal dose) to lethal infections with E. faecalis CP-1 and that prior dexamethasone treatment partially compensated for adrenalectomy. In marked contrast to these findings, however, adrenalectomy did not substantially increase susceptibility to lethal E. faecalis K9 infection. Further, preinfection with E. faecalis CP-1 1 hour before infection with E. faecalis K9 did not protect mice from lethal E. faecalis K9 infections. Collectively, these studies indicate that the host can generate a glucocorticoid response to E. faecalis infection that suppresses TNF-α production. Further, this glucocorticoid response can protect the host from potentially lethal E. faecalis infections, but different strains show heterogeneity with respect to the extent of protection afforded by the adrenal-glucocorticoid response.

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Mycoplasma pneumoniae-Derived Lipopeptides Induce Acute Inflammatory Responses in the Lungs of Mice

Infection and Immunity ◽

10.1128/iai.00955-07 ◽

2007 ◽

Vol 76 (1) ◽

pp. 270-277 ◽

Cited By ~ 40

Author(s):

Takashi Shimizu ◽

Yutaka Kida ◽

Koichi Kuwano

Keyword(s):

Mycoplasma Pneumoniae ◽

Inflammatory Responses ◽

Lavage Fluid ◽

Peritoneal Macrophages ◽

Necrosis Factor Alpha ◽

Chemokine Production ◽

Cytokines And Chemokines ◽

Tnf Α ◽

Mouse Peritoneal Macrophages

ABSTRACT The pathogenesis of Mycoplasma pneumoniae infection is considered to be in part attributable to excessive immune responses. In this study, we investigated whether synthetic lipopeptides of subunit b of F0F1-type ATPase (F0F1-ATPase), NF-κB-activating lipoprotein 1 (N-ALP1), and N-ALP2 (named FAM20, sN-ALP1, and sN-ALP2, respectively) derived from M. pneumoniae induce cytokine and chemokine production and leukocyte infiltration in vivo. Intranasal administration of FAM20 and sN-ALP2 induced infiltration of leukocyte cells and production of chemokines and cytokines in bronchoalveolar lavage fluid, but sN-ALP1 failed to do so. The activity of FAM20 was notably higher than that of sN-ALP2. FAM20 and sN-ALP2 induced tumor necrosis factor alpha (TNF-α) through Toll-like receptor 2 in mouse peritoneal macrophages. Moreover, in the range of low concentrations of lipopeptides, FAM20 showed relatively high activity of inducing TNF-α in mouse peritoneal macrophages compared to synthetic lipopeptides such as MALP-2 and FSL-1, derived from Mycoplasma fermentans and Mycoplasma salivarium, respectively. These findings indicate that the F0F1-ATPase might be a key molecule in inducing cytokines and chemokines contributing to inflammatory responses during M. pneumoniae infection in vivo.

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Salivary Cytokines and Airways Disease Severity in Patients with Cystic Fibrosis

Diagnostics ◽

10.3390/diagnostics10040222 ◽

2020 ◽

Vol 10 (4) ◽

pp. 222 ◽

Cited By ~ 3

Author(s):

Alice Castaldo ◽

Paola Iacotucci ◽

Vincenzo Carnovale ◽

Roberta Cimino ◽

Renato Liguori ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Disease ◽

Healthy Subjects ◽

Inferior Turbinate ◽

Lavage Fluid ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Cytokine Levels ◽

Inferior Turbinate Hypertrophy ◽

Sinonasal Disease

About 50% of patients with cystic fibrosis (CF) have sinonasal complications, which include inferior turbinate hypertrophy (NTH) and/or nasal polyposis (NP), and different degrees of lung disease, which represents the main cause of mortality. Monitoring of sinonasal disease requires complex instrumental procedures, while monitoring of lung inflammation requires invasive collection of bronchoalveolar lavage fluid. The aim of this study was to investigate the associations between salivary cytokines levels and CF-related airway diseases. Salivary biochemical parameters and cytokines, i.e., interleukin-6 (IL-6), IL-8, and tumor necrosis factor alpha (TNF-α), were analyzed in resting saliva from healthy subjects and patients with CF. Patients with CF showed significantly higher levels of salivary chloride, IL-6, IL-8, and TNF-α and lower calcium levels than healthy subjects. Among patients with CF, IL-6 and IL-8 were significantly higher in patients with NTH, while TNF-α was significantly lower in patients with NP. A decreasing trend of TNF-α in patients with severe lung disease was also observed. On the other hand, we did not find significant correlation between cytokine levels and Pseudomonas aeruginosa or Stenotrophomonas maltophilia colonization. These preliminary results suggest that salivary IL-6 and IL-8 levels increase during the acute phase of sinonasal disease (i.e., NTH), while the end stages of pulmonary disease and sinonasal disease (i.e., NP) show decreased TNF-α levels.

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The Protective Effect of Ceramide in Immature Rat Brain Hypoxia—Ischemia Involves Up-Regulation of BCL-2 and Reduction of TUNEL-Positive Cells

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200101000-00005 ◽

2001 ◽

Vol 21 (1) ◽

pp. 34-40 ◽

Cited By ~ 54

Author(s):

Yong Chen ◽

Irene Ginis ◽

John M. Hallenbeck

Keyword(s):

Infarct Volume ◽

Treated Group ◽

Protective Role ◽

Necrosis Factor Alpha ◽

Immature Rat ◽

Tnf Α ◽

Hypoxia Ischemia ◽

Old Rats ◽

Factor Alpha ◽

The Right

Preconditioning brain with tumor necrosis factor alpha (TNF-α) can induce tolerance to experimental hypoxia and stroke and ceramide is a downstream messenger in the TNF-α signaling pathway. A hypoxic-ischemic (HI) insult in the immature rat injures brain primarily through apoptosis. Apoptosis is regulated by Bcl-2 family proteins. The authors explored whether ceramide protects against HI in the immature rat, and whether Bcl-2 family protein expression is involved. Hypoxia-ischemia was produced in seven-day-old rats by ligating the right carotid artery, followed by 2 hours of 8% oxygen exposure. Thirty minutes after HI, C2-ceramide (150 μg/kg) was injected intraventricularly. Infarct volume was measured 5 days later. C2-ceramide reduced HI-induced brain damage by 45% to 65% compared with HI/dimethyl sulfoxide (DMSO) (vehicle control) or HI only groups. In separate experiments, brains of sham-operated control and HI only animals and animals subjected to HI plus C2-ceramide or DMSO infusion were sampled 6 hours, 24 hours, and 5 days after treatments and analyzed for Bcl-2, Bcl-xl, and Bax expression (Western blotting), and apoptosis (TUNEL assay). Augmented Bcl-2 and Bcl-xl levels in the C2-ceramide treated group were associated with a significant decrease in TUNEL-positive cells. The results support a protective role for ceramide in neonatal HI.

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Endogenous Interleukin-6 Plays a Crucial Protective Role in Streptococcal Toxic Shock Syndrome via Suppression of Tumor Necrosis Factor Alpha Production

Infection and Immunity ◽

10.1128/iai.73.6.3745-3748.2005 ◽

2005 ◽

Vol 73 (6) ◽

pp. 3745-3748 ◽

Cited By ~ 31

Author(s):

Hongyan Diao ◽

Masashi Kohanawa

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Interleukin 6 ◽

Tumor Necrosis ◽

Protective Role ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Deficient Mice ◽

Necrosis Factor

ABSTRACT During a Streptococcus pyogenes infection in interleukin-6 (IL-6)-deficient mice, there is elevation of serum tumor necrosis factor alpha (TNF-α) levels, muscular necrosis, and death compared with infection of C57BL/6 mice. Anti-TNF-α monoclonal antibody treatment decreased mortality and muscular necrosis in the infected IL-6-deficient mice. These results suggest that IL-6 plays a crucial protective role via suppression of TNF-α production in S. pyogenes infection.

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Release of tumour necrosis factor alpha into bronchial alveolar lavage fluid following antigen challenge in passively sensitized guinea-pigs

Mediators of Inflammation ◽

10.1155/s0962935192000644 ◽

1992 ◽

Vol 1 (6) ◽

pp. 425-428 ◽

Cited By ~ 2

Author(s):

D. E. Kelly ◽

M. Denis ◽

D. F. Biggs

Keyword(s):

Tumour Necrosis Factor ◽

Guinea Pigs ◽

Tumour Necrosis ◽

Interleukin 1 ◽

Lavage Fluid ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Α ◽

Bronchial Alveolar Lavage ◽

Necrosis Factor

Five groups of ten female guinea-pigs were passively sensitized against ovalbumin (OA) (n = 9) or control guinea-pig serum (n = 1). 24 h later, they received mepyramine (0.5 mg/kg, i.p.) and 30 min later inhaled aerosols of: (A) OA (2 in 0.9% saline, 8 min, n = 4/9); (B) saline (40 min, n = 4/9); (C) LPS (40 min, Escherichia coli 0111:B4, 150 ng/kg in PBS, n = 1/9); and (D) the control animal was treated as in (C) (n = 1). Their tracheas were cannulated under pentobarbital anaesthesia and bronchial alveolar lavage (BAL) was performed with 2 × 5 ml PBS containing BSA (1%) (n = 1 group), or BSA (1%) and aprotinin (1000 KIU/ml) (n = 4 groups), at 30, 60, 90 or 120 min post-inhalations. BAL fluids recovered were centrifuged, the supernatants recovered and frozen until assayed for tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6). No TNF-α could be detected unless aprotinin was present in the lavaging solution. BAL fluid from OA-sensitized and control animals that had inhaled LPS contained high levels of TNF-α that peaked at 90 min. BAL fluid from OA sensitized animals that inhaled OA aerosols contained no detectable TNF-α at 30 min, but it was found in increasing amounts at 60, 90 and 120 min; TNF-α was not detected in fluid from any of the animals that inhaled saline. As BAL fluids were toxic to the cells used in the assays, neither IL-1 nor IL-6 could be measured. We conclude that the monokine TNF-α is released into BAL fluid following anaphylactic challenge of passively sensitized guinea-pigs. The presence of the antiprotease, aprotinin, in the lavaging solution is essential for the detection and measurement of TNF-α in BAL fluid.

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Cytokine Networking in Lungs of Immunocompetent Mice in Response to Inhaled Aspergillus fumigatus

Infection and Immunity ◽

10.1128/iai.69.3.1554-1560.2001 ◽

2001 ◽

Vol 69 (3) ◽

pp. 1554-1560 ◽

Cited By ~ 79

Author(s):

Joan K. Brieland ◽

Craig Jackson ◽

Fred Menzel ◽

David Loebenberg ◽

Anthony Cacciapuoti ◽

...

Keyword(s):

Aspergillus Fumigatus ◽

Lung Tissue ◽

Lavage Fluid ◽

Pcr Analysis ◽

Pulmonary Aspergillosis ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Ifn Γ ◽

Immunocompetent Mice

ABSTRACT Cytokine networking in the lung in response to inhaledAspergillus fumigatus was assessed using a murine model of primary pulmonary aspergillosis in immunocompetent Crl:CF-1 mice. Inhalation of virulent A. fumigatus (6 × 106 CFU) resulted in the induction of interleukin 18 (IL-18), tumor necrosis factor alpha (TNF-α), IL-12, and gamma interferon (IFN-γ) protein in bronchoalveolar lavage fluid and/or lung tissue. Induction of immunoreactive IL-18 preceded induction of TNF-α protein, which preceded induction of immunoreactive IL-12 and IFN-γ. Real-time reverse transcriptase (RT) PCR analysis of infected lung tissue demonstrated that induction of IL-18 protein also preceded induction of pulmonary TNF-α, IL-12, and IFN-γ mRNAs. Mice were subsequently treated with cytokine-specific neutralizing monoclonal antibodies (MAbs) to the IL-18 receptor (anti-IL-18R MAb), TNF-α (anti-TNF-α MAb), IL-12 (anti-IL-12 MAb), and/or IFN-γ (anti-IFN-γ MAb), and effects on intrapulmonary cytokine activity and growth of A. fumigatuswere assessed in infected lung homogenates. Simultaneous neutralization of IL-12 and IL-18 resulted in decreased levels of immunoreactive TNF-α, while neutralization of IL-18, TNF-α, or IL-12 alone or of IL-18 and IL-12 together resulted in decreased levels of immunoreactive IFN-γ. Simultaneous neutralization of IL-12 and IL-18 or neutralization of TNF-α alone or in combination with IL-12, IL-18, or IFN-γ also resulted in a significant increase inA. fumigatus CFU in lung tissue. Taken together, these results demonstrate that endogenous IL-18, IL-12, and TNF-α, through their modulatory effects on both intrapulmonary cytokine activity and growth of A. fumigatus, play key roles in host defense against primary pulmonary aspergillosis.

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Analysis of Virulence and Inflammatory Potential of Shigella flexneri Purine Biosynthesis Mutants

Infection and Immunity ◽

10.1128/iai.71.12.7002-7013.2003 ◽

2003 ◽

Vol 71 (12) ◽

pp. 7002-7013 ◽

Cited By ~ 31

Author(s):

Antonella Cersini ◽

Maria Celeste Martino ◽

Irene Martini ◽

Giacomo Rossi ◽

Maria Lina Bernardini

Keyword(s):

Animal Models ◽

Shigella Flexneri ◽

Lethal Dose ◽

Purine Biosynthesis ◽

Pcr Analysis ◽

Wild Type ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Virulence Attenuation ◽

Ifn Γ

ABSTRACT Several Shigella flexneri mutants with defects in aromatic amino acid and/or purine biosynthesis have been evaluated as vaccines in humans or in animal models. To be suitable as a vaccine, a mutant has to show virulence attenuation, minimal reactogenicity, and a good immunogenic potential in animal models. With this aim, we have constructed five S. flexneri 5 (wild-type strain M90T) mutants with inactivation of one or two of the loci purEK, purHD, and guaBA, governing early or late steps of purine biosynthesis. The mutants have been analyzed in vitro in cell cultures and in vivo in the Sereny test and in the murine pulmonary model of shigellosis. M90T guaBA, M90T guaBA purEK, M90T guaBA purHD, and M90T purHD purEK gave a negative result in the Sereny test. In contrast, in the murine pulmonary model all of the strains had the same 50% lethal dose as the wild type, except M90T guaBA purHD, which did not result in death of the animals. Nevertheless, bacterial counts in infected lungs, immunohistochemistry, and reverse transcription-PCR analysis of mRNAs for tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), interleukin-1β (IL-1β), IL-6, IL-12, and inducible nitric oxide synthase (iNOS) revealed significant differences among the strains. At 72 h postinfection, M90T guaBA purHD still induced proinflammatory cytokines and factors such as IL-1β, IL-6, TNF-α, and iNOS, along with cytokines such as IL-12 and IFN-γ. Moreover, in the absence of evident lesions in murine tissues, this mutant highly stimulated major histocompatibility complex class II expression, showing a significant ability to activate the innate immunity of the host.

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MyD88-Dependent Signaling Contributes to Protection following Bacillus anthracis Spore Challenge of Mice: Implications for Toll-Like Receptor Signaling

Infection and Immunity ◽

10.1128/iai.73.11.7535-7540.2005 ◽

2005 ◽

Vol 73 (11) ◽

pp. 7535-7540 ◽

Cited By ~ 41

Author(s):

Molly A. Hughes ◽

Candace S. Green ◽

Lisa Lowchyj ◽

Gloria M. Lee ◽

Vanessa K. Grippe ◽

...

Keyword(s):

Bacillus Anthracis ◽

Protective Role ◽

Innate Immune ◽

Hek293 Cells ◽

In Vivo Studies ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Anthrax Infection ◽

Host Innate Immune Response

ABSTRACT Bacillus anthracis is a spore-forming, gram-positive organism that is the causative agent of the disease anthrax. Recognition of Bacillus anthracis by the host innate immune system likely plays a key protective role following infection. In the present study, we examined the role of TLR2, TLR4, and MyD88 in the response to B. anthracis. Heat-killed Bacillus anthracis stimulated TLR2, but not TLR4, signaling in HEK293 cells and stimulated tumor necrosis factor alpha (TNF-α) production in C3H/HeN, C3H/HeJ, and C57BL/6J bone marrow-derived macrophages. The ability of heat-killed B. anthracis to induce a TNF-α response was preserved in TLR2−/− but not in MyD88−/− macrophages. In vivo studies revealed that TLR2−/− mice and TLR4-deficient mice were resistant to challenge with aerosolized Sterne strain spores but MyD88−/− mice were as susceptible as A/J mice. We conclude that, although recognition of B. anthracis occurs via TLR2, additional MyD88-dependent pathways contribute to the host innate immune response to anthrax infection.

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Protective Role of Nitric Oxide inStaphylococcus aureus Infection in Mice

Infection and Immunity ◽

10.1128/iai.66.3.1017-1022.1998 ◽

1998 ◽

Vol 66 (3) ◽

pp. 1017-1022 ◽

Cited By ~ 65

Author(s):

Sanae Sasaki ◽

Tomisato Miura ◽

Shinsuke Nishikawa ◽

Kyogo Yamada ◽

Mayuko Hirasue ◽

...

Keyword(s):

Nitric Oxide ◽

Spleen Cell ◽

Cell Cultures ◽

Protective Role ◽

Inos Mrna ◽

No Production ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Ifn Γ

ABSTRACT This study was carried out to determine the role of nitric oxide (NO) in Staphylococcus aureus infection in mice. NO production in spleen cell cultures was induced by heat-killed S. aureus. Expression of mRNA of the inducible isoform of NO synthase (iNOS) was induced in the spleens and kidneys of S. aureus-infected mice. When mice were treated with monoclonal antibodies (MAbs) against tumor necrosis factor alpha (TNF-α) or gamma interferon (IFN-γ) before S. aureus infection, the induction of iNOS mRNA expression in the kidneys was inhibited. These MAbs also inhibited NO production in spleen cell cultures stimulated with heat-killed S. aureus. NO production in the spleen cell cultures and levels of urinary nitrate plus nitrite were suppressed by treatment with aminoguanidine (AG), a selective inhibitor of iNOS. The survival rates of AG-treated mice were significantly decreased by either lethal or sublethal S. aureusinfections. However, an effect of AG administration on bacterial growth was not observed in the spleens and kidneys of mice during either type of infection. Production of TNF-α and IFN-γ was not affected by AG treatment in vitro and in vivo. These results suggest that NO plays an important role in protection from lethality by the infection, but the protective role of NO in host resistance against S. aureusinfection was not proved. Moreover, our results show that TNF-α and IFN-γ regulate NO production while NO may not be involved in the regulation of the production of these cytokines during S. aureus infection.

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Characterization of a Murine Model of Ureaplasma urealyticum Pneumonia

Infection and Immunity ◽

10.1128/iai.70.10.5721-5729.2002 ◽

2002 ◽

Vol 70 (10) ◽

pp. 5721-5729 ◽

Cited By ~ 27

Author(s):

Rose M. Viscardi ◽

Jennifer Kaplan ◽

Judith C. Lovchik ◽

Ju Ren He ◽

Lisa Hester ◽

...

Keyword(s):

Ureaplasma Urealyticum ◽

Tissue Injury ◽

Lavage Fluid ◽

Interleukin 10 ◽

Broth Culture ◽

Necrosis Factor Alpha ◽

Monocyte Chemoattractant Protein 1 ◽

Chronic Inflammatory Response ◽

Tnf Α ◽

Macrophage Colony

ABSTRACT Ureaplasma urealyticum respiratory tract colonization in preterm infants has been associated with a high incidence of pneumonia and the development of bronchopulmonary dysplasia. However, study of this human pathogen has been hampered by the absence of animal models. We have developed the first juvenile mouse model of Ureaplasma pneumonia and characterized the histopathology during the month following inoculation. C3H/HeN mice were inoculated intratracheally with a mouse-adapted clinical Ureaplasma isolate (biovar 2) or sham inoculated with 10B broth. Culture of lung homogenates and PCR of DNA from bronchoalveolar lavage fluid (BAL) confirmed the presence of Ureaplasma in 100% of inoculated animals at 1 day, 60% at 2 days, 50% at 3 days, and 25% at 7 and 14 days. Ureaplasma was undetectable 28 days postinoculation. There were marked changes in BAL and interstitial-cell composition with increased number of polymorphonuclear leukocytes 1 to 2 days and 14 days postinoculation and macrophages at 2 and 14 days postinoculation. The Ureaplasma infection caused a persistent focal loss of airway ciliated epithelium and a mild increase in interstitial cellularity. There were no differences in BAL protein concentration during the first 28 days, suggesting that pulmonary vascular endothelial barrier integrity remained intact. Comparison of BAL cytokine and chemokine concentrations revealed low levels of tumor necrosis factor alpha (TNF-α) at 3 days and monocyte chemoattractant protein 1 at 7 days in Ureaplasma-infected mice but a trend toward increased TNF-α at 14 days and increased granulocyte-macrophage colony-stimulating factor and interleukin-10 at 28 days. These data suggest that Ureaplasma alone may cause limited inflammation and minimal tissue injury in the early phase of infection but may promote a mild chronic inflammatory response in the later phase of infection (days 14 to 28), similar to the process that occurs in human newborns.

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