scholarly journals Extracellular Vesicles from Cryptococcus neoformans Modulate Macrophage Functions

2010 ◽  
Vol 78 (4) ◽  
pp. 1601-1609 ◽  
Author(s):  
Débora L. Oliveira ◽  
Célio G. Freire-de-Lima ◽  
Joshua D. Nosanchuk ◽  
Arturo Casadevall ◽  
Marcio L. Rodrigues ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Extracellular Vesicles ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Biologically Active ◽  
Host Cells ◽  
Phagocytic Cells ◽  
Necrosis Factor Alpha

ABSTRACT Cryptococcus neoformans and distantly related fungal species release extracellular vesicles that traverse the cell wall and contain a varied assortment of components, some of which have been associated with virulence. Previous studies have suggested that these extracellular vesicles are produced in vitro and during animal infection, but the role of vesicular secretion during the interaction of fungi with host cells remains unknown. In this report, we demonstrate by fluorescence microscopy that mammalian macrophages can incorporate extracellular vesicles produced by C. neoformans. Incubation of cryptococcal vesicles with murine macrophages resulted in increased levels of extracellular tumor necrosis factor alpha (TNF-α), interleukin-10 (IL-10), and transforming growth factor β (TGF-β). Vesicle preparations also resulted in a dose-dependent stimulation of nitric oxide production by phagocytes, suggesting that vesicle components stimulate macrophages to produce antimicrobial compounds. Treated macrophages were more effective at killing C. neoformans yeast. Our results indicate that the extracellular vesicles of C. neoformans can stimulate macrophage function, apparently activating these phagocytic cells to enhance their antimicrobial activity. These results establish that cryptococcal vesicles are biologically active.

scholarly journals Endothelial Cells Require STAT3 for Protection against Endotoxin-induced Inf lammation

2003 ◽  
Vol 198 (10) ◽  
pp. 1517-1525 ◽  
Author(s):  
Arihiro Kano ◽  
Michael J. Wolfgang ◽  
Qian Gao ◽  
Joerg Jacoby ◽  
Gui-Xuan Chai ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transforming Growth Factor ◽  
Endotoxic Shock ◽  
Transforming Growth Factor Β ◽  
Organ Damage ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Protective Function ◽  
Lps Challenge

Endothelial cells (ECs) are believed to be an important component in the protection from lipopolysaccharide (LPS)-induced endotoxic shock. However, the cellular and molecular mechanism is not well defined. Here, we report that signal transducer and activator of transcription (STAT) 3 is an essential regulator of the antiinflammatory function of ECs in systemic immunity. Because STAT3 deficiency results in early embryonic lethality, we have generated mice with a conditional STAT3 deletion in endothelium (STAT3E−/−). STAT3E−/− mice are healthy and fertile, and isolated ECs initiate normal tube formation in vitro. Conditional endothelial but not organ-specific (i.e., hepatocyte or cardiomyocyte) STAT3 knockout mice show an increased susceptibility to lethality after LPS challenge. The LPS response in STAT3E−/− mice shows exaggerated inflammation and leukocyte infiltration in multiple organs combined with elevated activity of serum alanine aminotransferase and aspartate aminotransferase, indicating organ damage. Concomitantly, proinflammatory cytokines are produced at an exaggerated level and for a prolonged period. This defect cannot be explained by lack of antiinflammatory cytokines, such as interleukin 10 and transforming growth factor β. Instead, we have shown that a soluble activity derived from endothelia and dependent on STAT3 is critical for suppression of interferon γ. These data define STAT3 signaling within endothelia as a critical antiinflammatory mediator and provide new insight to the protective function of ECs in inflammation.

scholarly journals Effects of Gamma Interferon, Interleukin-10, and Transforming Growth Factor β on the Survival of Mycobacterium avium subsp. paratuberculosis in Monocyte-Derived Macrophages from Naturally Infected Cattle

2004 ◽  
Vol 72 (4) ◽  
pp. 1974-1982 ◽  
Author(s):  
M. S. Khalifeh ◽  
J. R. Stabel
Keyword(s):  
Growth Factor ◽  
Cell Cultures ◽  
Mycobacterium Avium ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Ifn Γ ◽  
Culture Supernatants

ABSTRACT Gamma interferon (IFN-γ) plays a significant role in the control of mycobacterial infections, including Mycobacterium avium subsp. paratuberculosis. However, the contribution of other immunoregulatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor β (TGF-β), in Johne's disease has not been investigated as yet. In this study, we examined the effects of in vivo and in vitro infection with M. avium subsp. paratuberculosis on the production of IFN-γ, IL-10, and TGF-β by peripheral blood mononuclear cells (PBMC). We also examined the effects of exogenous IFN-γ, IL-10, and TGF-β on M. avium subsp. paratuberculosis survival in the cell cultures. PBMC obtained from naturally infected cows, regardless of their disease status, specifically upregulated IL-10 and TGF-β in culture supernatants in response to stimulation with live M. avium subsp. paratuberculosis. Nonstimulated PBMC recovered from subclinically infected animals secreted the lowest levels of TGF-β, but after stimulation with live M. avium subsp. paratuberculosis, TGF-β levels in the culture supernatants increased to levels similar to that produced by PBMC from healthy animals. The numbers of viable M. avium subsp. paratuberculosis recovered from cultures from naturally infected animals were higher than those from healthy cows after in vitro infection with M. avium subsp. paratuberculosis. The addition of exogenous IL-10 and TGF-β to PBMC isolated from healthy cows inhibited the bactericidal activity of these cells as evidenced by the increased number of viable M. avium subsp. paratuberculosis recovered from these cultures compared to cell cultures containing medium alone. These data suggest important immune regulatory roles for IL-10 and TGF-β during infection with M. avium subsp. paratuberculosis that may be directly related to their effects on macrophage activation and killing of M. avium subsp. paratuberculosis.

scholarly journals Phenotypic Switching in Cryptococcus neoformans Contributes to Virulence by Changing the Immunological Host Response

2008 ◽  
Vol 76 (9) ◽  
pp. 4322-4331 ◽  
Author(s):  
Abraham Guerrero ◽  
Bettina C. Fries
Keyword(s):  
Inflammatory Response ◽  
Cryptococcus Neoformans ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Interleukin 10 ◽  
Host Responses ◽  
Phenotypic Switching ◽  
Wild Type ◽  
Necrosis Factor Alpha

ABSTRACT Cryptococcus neoformans is an encapsulated opportunistic organism that can undergo phenotypic switching. In this process, the parent smooth colony (SM) switches to a more virulent mucoid colony (MC) variant. The host responses mounted against the SM and MC variants differ, and lower tissue interleukin 10 (IL-10) levels are consistently observed in lungs of MC-infected C57BL/6 and BALB/c mice. This suggested different roles of this cytokine in SM and MC infections. The objective of this study was to compare survival rates and characterize the host responses of SM- and MC-infected IL-10-depleted (IL-10−/−) mice, which exhibit a Th1-polarized immune response and are considered resistant hosts. As expected, SM-infected IL-10−/− mice survived longer than wild-type mice, whereas MC-infected IL-10−/− mice did not exhibit a survival benefit. Consistent with this observation, we demonstrated marked differences in the inflammatory responses of SM- and MC-infected IL-10−/− and wild-type mice. This included a more Th1-polarized inflammatory response with enhanced recruitment of macrophages and natural killer and CD8 cells in MC- than in SM-infected IL-10−/− and wild-type mice. In contrast, both SM-infected IL-10−/− and wild-type mice exhibited higher recruitment of CD4 cells, consistent with enhanced survival and differences in recruitment and Th1/Th2 polarization. Lung tissue levels of IL-21, IL-6, IL-4, transforming growth factor beta, IL-12, and gamma interferon were higher in MC-infected IL-10−/− and wild-type mice than in SM-infected mice, whereas tumor necrosis factor alpha levels were higher in SM-infected IL-10−/− mice. In conclusion, the MC variant elicits an excessive inflammatory response in a Th1-polarized host environment, and therefore, the outcome is negatively affected by the absence of IL-10.

scholarly journals Relative Importance of NF-κB p50 in Mycobacterial Infection

2001 ◽  
Vol 69 (11) ◽  
pp. 7100-7105 ◽  
Author(s):  
Hiroyuki Yamada ◽  
Satoru Mizuno ◽  
Mohammad Reza-Gholizadeh ◽  
Isamu Sugawara
Keyword(s):  
Transforming Growth Factor ◽  
Interleukin 2 ◽  
Transforming Growth Factor Β ◽  
Mycobacterial Infection ◽  
Host Cells ◽  
Mrna Levels ◽  
Necrosis Factor Alpha ◽  
Airborne Infection ◽  
Normal Ranges

ABSTRACT To understand the role of NF-κB in the development of murine tuberculosis in vivo, NF-κB p50 knockout mice were infected withMycobacterium tuberculosis by placing them in the exposure chamber of an airborne-infection apparatus. These mice developed multifocal necrotic pulmonary lesions or lobar pneumonia. Compared with the levels in wild-type mice, pulmonary inducible nitric oxide synthase, interleukin-2 (IL-2), gamma interferon, and tumor necrosis factor alpha mRNA levels were significantly low but expression of IL-10 and transforming growth factor β mRNAs were within the normal ranges. The pulmonary IL-6 mRNA expression level was higher. Therefore, NF-κB and its interaction with host cells play an important role in the pathogenesis of tuberculosis.

scholarly journals Differential Modulatory Effects of Clarithromycin on the Production of Cytokines by a Tumor

1999 ◽  
Vol 43 (11) ◽  
pp. 2787-2789 ◽  
Author(s):  
Kazuhiko Sassa ◽  
Yutaka Mizushima ◽  
Masashi Kobayashi
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Mammary Adenocarcinoma ◽  
Necrosis Factor Alpha ◽  
Adenocarcinoma Cells ◽  
The Matrix ◽  
Factor Alpha ◽  
Metalloproteinase 9

ABSTRACT In vitro treatment with clarithromycin inhibited the expression of the matrix metalloproteinase-9, transforming growth factor β, and tumor necrosis factor alpha genes in 13762NF rat mammary adenocarcinoma cells. Transient enhancement, rather than inhibition, was observed for the interleukin-6 gene, and no significant change was observed for the tissue inhibitor of metalloproteinase-2 gene. Such an effect was not observed for cefotiam or gentamicin.

scholarly journals Enhanced Replication of Leishmania amazonensis Amastigotes in Gamma Interferon-Stimulated Murine Macrophages: Implications for the Pathogenesis of Cutaneous Leishmaniasis

2004 ◽  
Vol 72 (2) ◽  
pp. 988-995 ◽  
Author(s):  
Hai Qi ◽  
Jiaxiang Ji ◽  
Nanchaya Wanasen ◽  
Lynn Soong
Keyword(s):  
Leishmania Major ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Leishmania Amazonensis ◽  
Promoting Effect ◽  
Necrosis Factor Alpha ◽  
Different Temperatures ◽  
Ifn Γ

ABSTRACT During Leishmania major infection in mice, gamma interferon (IFN-γ) plays an essential role in controlling parasite growth and disease progression. In studies designed to ascertain the role of IFN-γ in Leishmania amazonensis infection, we were surprised to find that IFN-γ could promote L. amazonensis amastigote replication in macrophages (MΦs), although it activated MΦs to kill promastigotes. The replication-promoting effect of IFN-γ on amastigotes was independent of the source and genetic background of MΦs, was apparently not affected by surface opsonization of amastigotes, was not mediated by interleukin-10 or transforming growth factor β, and was observed at different temperatures. Consistent with the different fates of promastigotes and amastigotes in IFN-γ-stimulated MΦs, L. amazonensis-specific Th1 transfer helped recipient mice control L. amazonensis infection established by promastigotes but not L. amazonensis infection established by amastigotes. On the other hand, IFN-γ could stimulate MΦs to limit amastigote replication when it was coupled with lipopolysaccharides but not when it was coupled with tumor necrosis factor alpha. Thus, IFN-γ may play a bidirectional role at the level of parasite-MΦ interactions; when it is optimally coupled with other factors, it has a protective effect against infection, and in the absence of such synergy it promotes amastigote growth. These results reveal a quite unexpected aspect of the L. amazonensis parasite and have important implications for understanding the pathogenesis of the disease and for developing vaccines and immunotherapies.

scholarly journals Role of Hcp, a type 6 secretion system effector, of Aeromonas hydrophila in modulating activation of host immune cells

Microbiology ◽  
2010 ◽  
Vol 156 (12) ◽  
pp. 3678-3688 ◽  
Author(s):  
Giovanni Suarez ◽  
Johanna C. Sierra ◽  
Michelle L. Kirtley ◽  
Ashok K. Chopra
Keyword(s):  
Mouse Model ◽  
Aeromonas Hydrophila ◽  
Transforming Growth Factor ◽  
Interleukin 10 ◽  
Secretion System ◽  
Bacterial Virulence ◽  
Host Cells ◽  
Extracellular Milieu

Recently, we reported that the type 6 secretion system (T6SS) of Aeromonas hydrophila SSU plays an important role in bacterial virulence in a mouse model, and immunization of animals with the T6SS effector haemolysin co-regulated protein (Hcp) protected them against lethal infections with wild-type bacteria. Additionally, we showed that the mutant bacteria deleted for the vasH gene within the T6SS gene cluster did not express the hcp gene, while the vasK mutant could express and translocate Hcp, but was unable to secrete it into the extracellular milieu. Both of these A. hydrophila SSU mutants were readily phagocytosed by murine macrophages, pointing to the possible role of the secreted form of Hcp in the evasion of the host innate immunity. By using the ΔvasH mutant of A. hydrophila, our in vitro data showed that the addition of exogenous recombinant Hcp (rHcp) reduced bacterial uptake by macrophages. These results were substantiated by increased bacterial virulence when rHcp was added along with the ΔvasH mutant in a septicaemic mouse model of infection. Analysis of the cytokine profiling in the intraperitoneal lavage as well as activation of host cells after 4 h of infection with the ΔvasH mutant supplemented with rHcp indicated that this T6SS effector inhibited production of pro-inflammatory cytokines and induced immunosuppressive cytokines, such as interleukin-10 and transforming growth factor-β, which could circumvent macrophage activation and maturation. This mechanism of innate immune evasion by Hcp possibly inhibited the recruitment of cellular immune components, which allowed bacterial multiplication and dissemination in animals, thereby leading to their mortality.

scholarly journals Pathology of Plasmodium chabaudi chabaudi Infection and Mortality in Interleukin-10-Deficient Mice Are Ameliorated by Anti-Tumor Necrosis Factor Alpha and Exacerbated by Anti-Transforming Growth Factor β Antibodies

2003 ◽  
Vol 71 (9) ◽  
pp. 4850-4856 ◽  
Author(s):  
Ching Li ◽  
Latifu A. Sanni ◽  
Fakhreldin Omer ◽  
Eleanor Riley ◽  
Jean Langhorne
Keyword(s):  
Tumor Necrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Plasmodium Chabaudi ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Necrosis Factor

ABSTRACT Interleukin-10 (IL-10)-deficient (IL-10−/−) mice infected with Plasmodium chabaudi (AS) suffer a more severe disease and exhibit a higher rate of mortality than control C57BL/6 mice. Here, we show that a drop in body temperature to below 28°C and pronounced hypoglycemia of below 3 mM are reliable indicators of a lethal infection. Elevated inflammatory responses have been shown to accompany pathology in infected IL-10−/− mice. We show that neutralization of tumor necrosis factor alpha (TNF-α) in IL-10−/− mice abolishes mortality and ameliorates the hypothermia, weight loss, and anemia but does not affect the degree of hypoglycemia. These data suggest that TNF-α is involved in some of the pathology associated with a P. chabaudi infection in IL-10−/− mice but other factors play a role. IL-10−/− mice that survive a primary infection have been shown to control gamma interferon (IFN-γ) and TNF-α production, indicating that other cytokines or mechanisms may be involved in their down-regulation. Significantly higher levels of transforming growth factor β (TGF-β), a cytokine with such properties, are present in the plasma of infected IL-10−/− mice at a time that coincides with the disappearance of IFN-γ and TNF-α from the blood. Neutralization of TGF-β in IL-10−/− mice resulted in higher circulating amounts of TNF-α and IFN-γ, and all treated IL-10−/− mice died within 12 days with increased pathology but with no obvious increase in parasitemia. Our data suggest that a tight regulation of the balance between regulatory cytokines such as IL-10 and TGF-β and inflammatory cytokines such as IFN-γ and TNF-α is critical for survival in a mouse malaria infection.

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