scholarly journals Gamma Interferon Modulates CD95 (Fas) and CD95 Ligand (Fas-L) Expression and Nitric Oxide-Induced Apoptosis during the Acute Phase ofTrypanosoma cruzi Infection: a Possible Role in Immune Response Control

1999 ◽  
Vol 67 (8) ◽  
pp. 3864-3871 ◽  
Author(s):  
Gislâine A. Martins ◽  
Leda Q. Vieira ◽  
Fernando Q. Cunha ◽  
João S. Silva
Keyword(s):  
Nitric Oxide ◽  
Immune Response ◽  
Gamma Interferon ◽  
No Production ◽  
Apoptosis Induction ◽  
Lymphoproliferative Response ◽  
Response Control ◽  
Ifn Γ ◽  
Fas L

ABSTRACT We have previously shown that splenocytes from mice acutely infected with Trypanosoma cruzi exhibit high levels of nitric oxide (NO)-mediated apoptosis. In the present study, we used the gamma interferon (IFN-γ)-knockout (IFN-γ−/−) mice to investigate the role of IFN-γ in modulating apoptosis induction and host protection during T. cruzi infection in mice. IFN-γ−/− mice were highly susceptible to infection and exhibited significant reduction of NO production and apoptosis levels in splenocytes but normal lymphoproliferative response compared to the infected wild-type (WT) mice. Furthermore, IFN-γ modulates an enhancement of Fas and Fas-L expression after infection, since the infected IFN-γ−/− mice showed significantly lower levels of Fas and Fas-L expression. The addition of recombinant murine IFN-γ to spleen cells cultures from infected IFN-γ−/−mice increased apoptosis levels, Fas expression, and NO production. In the presence of IFN-γ and absence of NO, although Fas expression was maintained, apoptosis levels were significantly reduced but still higher than those found in splenocytes from uninfected mice, suggesting that Fas–Fas-L interaction could also play a role in apoptosis induction in T. cruzi-infected mice. Moreover, in vivo, the treatment of infected WT mice with the inducible nitric oxide synthase inhibitor aminoguanidine also led to decreased NO and apoptosis levels but not Fas expression, suggesting that IFN-γ modulates apoptosis induction by two independent and distinct mechanisms: induction of NO production and of Fas and Fas-L expression. We suggest that besides being of crucial importance in mediating resistance to experimentalT. cruzi infection, IFN-γ could participate in the immune response control through apoptosis modulation.

scholarly journals Induction of Gamma Interferon and Nitric Oxide by Truncated Pneumolysin That Lacks Pore-Forming Activity

2002 ◽  
Vol 70 (1) ◽  
pp. 107-113 ◽  
Author(s):  
Hisashi Baba ◽  
Ikuo Kawamura ◽  
Chikara Kohda ◽  
Takamasa Nomura ◽  
Yutaka Ito ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Neutralizing Antibody ◽  
Cytolytic Activity ◽  
Gamma Interferon ◽  
Full Length ◽  
No Production ◽  
Spleen Cells ◽  
Ifn Γ ◽  
Oxide Synthase

ABSTRACT Pneumolysin (PLY), an important virulence factor of Streptococcus pneumoniae, is known to exert various effects on the host immune cells, including cytokine induction, in addition to its known cytolytic activity as a member of the thiol-activated cytolysins. It is of interest to determine whether cytolytic activity is involved in triggering the cytokine production. In this study, we constructed full-length recombinant PLY and noncytolytic truncated PLYs with C-terminal deletions to examine the response of spleen cells to these PLY preparations. When cytolytic activity was blocked by treatment with cholesterol, full-length PLY was capable of inducing gamma interferon (IFN-γ) production. Truncated PLYs that originally exhibited no cytolytic activity were also active in IFN-γ induction. Therefore, the IFN-γ-inducing ability of PLY appeared to be independent of the cytolytic activity. Furthermore, IFN-γ-inducing preparations were also capable of inducing nitric oxide synthase expression and nitric oxide (NO) production, and the addition of neutralizing antibody to IFN-γ abolished the NO production. These results clearly demonstrated that PLY is capable of inducing IFN-γ production in spleen cells by a mechanism different from pore formation and that the induced IFN-γ stimulates NO production. These findings were discussed with reference to the contribution of PLY to the virulence of S. pneumoniae in vivo.

scholarly journals Resistance to Acute Babesiosis Is Associated with Interleukin-12- and Gamma Interferon-Mediated Responses and Requires Macrophages and Natural Killer Cells

2003 ◽  
Vol 71 (4) ◽  
pp. 2002-2008 ◽  
Author(s):  
Irma Aguilar-Delfin ◽  
Peter J. Wettstein ◽  
David H. Persing
Keyword(s):  
Nk Cells ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
No Production ◽  
Cytokine Responses ◽  
Early Production ◽  
Ifn Γ ◽  
Crucial Part

ABSTRACT We examined the role of the cytokines gamma interferon (IFN-γ) and interleukin-12 (IL-12) in the model of acute babesiosis with the WA1 Babesia. Mice genetically deficient in IFN-γ-mediated responses (IFNGR2KO mice) and IL-12-mediated responses (Stat4KO mice) were infected with the WA1 Babesia, and observations were made on the course of infection and cytokine responses. Levels of IFN-γ and IL-12 in serum increased 24 h after parasite inoculation. The augmented susceptibility observed in IFNGR2KO and Stat-4KO mice suggests that the early IL-12- and IFN-γ-mediated responses are involved in protection against acute babesiosis. Resistance appears to correlate with an increase in nitric oxide (NO) production. In order to assess the contribution of different cell subsets to resistance against the parasite, we also studied mice lacking B cells, CD4+ T cells, NK cells, and macrophages. Mice genetically deficient in B lymphocytes or CD4+ T lymphocytes were able to mount protective responses comparable to those of immunosufficient mice. In contrast, in vivo depletion of macrophages or NK cells resulted in elevated susceptibility to the infection. Our observations suggest that a crucial part of the response that protects from the pathogenic Babesia WA1 is mediated by macrophages and NK cells, probably through early production of IL-12 and IFN-γ, and induction of macrophage-derived effector molecules like NO.

scholarly journals Nitric Oxide-Mediated Regulation of Gamma Interferon-Induced Bacteriostasis: Inhibition and Degradation of Human Indoleamine 2,3-Dioxygenase

2004 ◽  
Vol 72 (5) ◽  
pp. 2723-2730 ◽  
Author(s):  
Christian Hucke ◽  
Colin R. MacKenzie ◽  
Koku D. Z. Adjogble ◽  
Osamu Takikawa ◽  
Walter Däubener
Keyword(s):  
Nitric Oxide ◽  
Gene Transcription ◽  
Kynurenine Pathway ◽  
Gamma Interferon ◽  
Human Cells ◽  
Epithelial Cell Line ◽  
Tryptophan Depletion ◽  
No Production ◽  
Indoleamine 2,3 Dioxygenase ◽  
Ifn Γ

ABSTRACT Tryptophan depletion resulting from indoleamine 2,3-dioxygenase (IDO) activity within the kynurenine pathway is one of the most prominent gamma interferon (IFN-γ)-inducible antimicrobial effector mechanisms in human cells. On the other hand, nitric oxide (NO) produced by the inducible isoform of NO synthase (iNOS) serves a more immunoregulatory role in human cells and thereby interacts with tryptophan depletion in a number of ways. We investigated the effects of NO on IDO gene transcription, protein synthesis, and enzyme activity as well as on IDO-mediated bacteriostasis in the human epithelial cell line RT4. IFN-γ-stimulated RT4 cells were able to inhibit the growth of Staphylococcus aureus in an IDO-mediated fashion, and this bacteriostatic effect was abolished by endogenously produced NO. These findings were supported by experiments which showed that IDO activity in extracts of IFN-γ-stimulated cells is inhibited by the chemical NO donors diethylenetriamine diazeniumdiolate, S-nitroso-l-cysteine, and S-nitroso-N-acetyl-d,l-penicillamine. Furthermore, we found that both endogenous and exogenous NO strongly reduced the level of IDO protein content in RT4 cells. This effect was not due to a decrease in IDO gene transcription or mRNA stability. By using inhibitors of proteasomal proteolytic activity, we showed that NO production led to an accelerated degradation of IDO protein in the proteasome. This is the first report, to our knowledge, that demonstrates that the IDO is degraded by the proteasome and that NO has an effect on IDO protein stability.

scholarly journals Inhibitory Effects of Nitric Oxide and Gamma Interferon on In Vitro and In Vivo Replication of Marek's Disease Virus

2000 ◽  
Vol 74 (8) ◽  
pp. 3605-3612 ◽  
Author(s):  
Zheng Xing ◽  
Karel A. Schat
Keyword(s):  
Nitric Oxide ◽  
Chicken Embryo Fibroblast ◽  
Gamma Interferon ◽  
Marek's Disease ◽  
No Production ◽  
Dependent Manner ◽  
Marek’S Disease ◽  
Dose Dependent

ABSTRACT The replication of Marek's disease herpesvirus (MDV) and herpesvirus of turkeys (HVT) in chicken embryo fibroblast (CEF) cultures was inhibited by the addition ofS-nitroso-N-acetylpenicillamine, a nitric oxide (NO)-generating compound, in a dose-dependent manner. Treatment of CEF culture, prepared from 11-day-old embryos, with recombinant chicken gamma interferon (rChIFN-γ) and lipopolysaccharide (LPS) resulted in production of NO which was suppressed by the addition ofN G-monomethyl l-arginine (NMMA), an inhibitor of inducible NO synthase (iNOS). Incubation of CEF cultures for 72 h prior to treatment with rChIFN-γ plus LPS was required for optimal NO production. Significant differences in NO production were observed in CEF derived from MDV-resistant N2a (major histocompatibility complex [MHC],B 21 B 21) and MDV-susceptible S13 (MHC,B 13 B 13) and P2a (MHC,B 19 B 19) chickens. N2a-derived CEF produced NO earlier and at higher levels than CEF from the other two lines. The lowest production of NO was detected in P2a-derived CEF. NO production in chicken splenocyte cultures followed a similar pattern, with the highest levels of NO produced in cultures from N2a chickens and the lowest levels produced in cultures from P2a chickens. Replication of MDV and HVT was significantly inhibited in CEF cultures treated with rChIFN-γ plus LPS and producing NO. The addition of NMMA to CEF treated with rChIFN-γ plus LPS reduced the inhibition. MDV infection of chickens treated withS-methylisothiourea, an inhibitor of iNOS, resulted in increased virus load compared to nontreated chickens. These results suggest that NO may play an important role in control of MDV replication in vivo.

scholarly journals Soluble Factors Released by Toxoplasma gondii-Infected Astrocytes Down-Modulate Nitric Oxide Production by Gamma Interferon-Activated Microglia and Prevent Neuronal Degeneration

2003 ◽  
Vol 71 (4) ◽  
pp. 2047-2057 ◽  
Author(s):  
Claudia Rozenfeld ◽  
Rodrigo Martinez ◽  
Rodrigo T. Figueiredo ◽  
Marcelo T. Bozza ◽  
Flávia R. S. Lima ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Toxoplasma Gondii ◽  
Neuronal Degeneration ◽  
Gamma Interferon ◽  
Common Finding ◽  
Prostaglandin E ◽  
No Production ◽  
Toxic Metabolite ◽  
Activated Microglia ◽  
Ifn Γ

ABSTRACT The maintenance of a benign chronic Toxoplasma gondii infection is mainly dependent on the persistent presence of gamma interferon (IFN-γ) in the central nervous system (CNS). However, IFN-γ-activated microglia are paradoxically involved in parasitism control and in tissue damage during a broad range of CNS pathologies. In this way, nitric oxide (NO), the main toxic metabolite produced by IFN-γ-activated microglia, may cause neuronal injury during T. gondii infection. Despite the potential NO toxicity, neurodegeneration is not a common finding during chronic T. gondii infection. In this work, we describe a significant down-modulation of NO production by IFN-γ-activated microglia in the presence of conditioned medium of T. gondii-infected astrocytes (CMi). The inhibition of NO production was paralleled with recovery of neurite outgrowth when neurons were cocultured with IFN-γ-activated microglia in the presence of CMi. Moreover, the modulation of NO secretion and the neuroprotective effect were shown to be dependent on prostaglandin E2 (PGE2) production by T. gondii-infected astrocytes and autocrine secretion of interleukin-10 (IL-10) by microglia. These events were partially eliminated when infected astrocytes were treated with aspirin and cocultures were treated with anti-IL-10 neutralizing antibodies and RP-8-Br cyclic AMP (cAMP), a protein kinase A inhibitor. Further, the modulatory effects of CMi were mimicked by the presence of exogenous PGE2 and by forskolin, an adenylate cyclase activator. Altogether, these data point to a T. gondii-triggered regulatory mechanism involving PGE2 secretion by astrocytes and cAMP-dependent IL-10 secretion by microglia. This may reduce host tissue inflammation, thus avoiding neuron damage during an established Th1 protective immune response.

scholarly journals Gamma Interferon Treatment of Patients with Chronic Granulomatous Disease Is Associated with Augmented Production of Nitric Oxide by Polymorphonuclear Neutrophils

1999 ◽  
Vol 6 (3) ◽  
pp. 420-424 ◽  
Author(s):  
Anders Åhlin ◽  
Gerd Lärfars ◽  
Göran Elinder ◽  
Jan Palmblad ◽  
Hans Gyllenhammar
Keyword(s):  
Nitric Oxide ◽  
Chronic Granulomatous Disease ◽  
Gamma Interferon ◽  
Polymorphonuclear Neutrophils ◽  
No Production ◽  
Granulomatous Disease ◽  
Reduced Frequency ◽  
No Release ◽  
Ifn Γ ◽  
Inducible Nitric Oxide

ABSTRACT Treatment with gamma-interferon (IFN-γ) is associated with reduced frequency and severity of infections in chronic granulomatous disease (CGD), but the mechanism is unknown. Since the inducible nitric oxide (NO) synthase can be amplified by IFN-γ in murine macrophages, for example, we hypothesized that IFN-γ might modulate NO release from polymorphonuclear neutrophils (PMNs) in patients with CGD. Eight patients with CGD and eight healthy controls were studied. Each patient was given either 50 or 100 μg of IFN-γ per m2 on two consecutive days. The production of NO fromN-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated PMNs was assessed as theN G-monomethyl-l-arginine-inhibitable oxidation of oxyhemoglobin to methemoglobin in the presence of catalase and superoxide dismutase. Prior to IFN-γ treatment, the PMNs from CGD patients produced 372 ± 27 (mean ± standard error of the mean) pmol of NO/106 PMNs at 45 min, while the control PMNs produced 343 ± 44 pmol. On day 1 after IFN-γ treatment, NO production increased to 132% ± 25% of that for controls, and on day 3 it reached 360% ± 37% (P < 0.001) of that for controls. On day 8, the values still remained higher, 280% ± 78% more than the control values. Likewise, the bactericidal capacity of PMNs increased on day 3. The present data show that IFN-γ treatment of CGD patients is associated with an increased production of NO from PMNs when activated by fMLP. Since these PMNs lack the capacity to produce superoxide anions, it is conceivable that this increase in NO release could be instrumental in augmenting host defense.

scholarly journals Leukotriene B4 Induces Nitric Oxide Synthesis in Trypanosoma cruzi-Infected Murine Macrophages and Mediates Resistance to Infection

2002 ◽  
Vol 70 (8) ◽  
pp. 4247-4253 ◽  
Author(s):  
A. Talvani ◽  
F. S. Machado ◽  
G. C. Santana ◽  
A. Klein ◽  
L. Barcelos ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Trypanosoma Cruzi ◽  
Leukotriene B4 ◽  
No Production ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT The production of nitric oxide (NO) by gamma interferon (IFN-γ)-activated macrophages is a major effector mechanism during experimental Trypanosoma cruzi infection. In addition to IFN-γ, chemoattractant molecules, such as platelet-activating factor (PAF) and CC chemokines, may also activate macrophages to induce NO and mediate the killing of T. cruzi in an NO-dependent manner. Here we investigated the ability of leukotriene B4 (LTB4) to induce the production of NO by macrophages infected with T. cruzi in vitro and whether NO mediated LTB4-induced parasite killing. The activation of T. cruzi-infected but not naive murine peritoneal macrophages with LTB4 induced the time- and concentration-dependent production of NO. In addition, low concentrations of LTB4 acted in synergy with IFN-γ to induce NO production. The NO produced mediated LTB4-induced microbicidal activity in macrophages, as demonstrated by the inhibitory effects of an inducible NO synthase inhibitor. LTB4-induced NO production and parasite killing were LTB4 receptor dependent and were partially blocked by a PAF receptor antagonist. LTB4 also induced significant tumor necrosis factor alpha (TNF-α) production, and blockade of TNF-α suppressed LTB4-induced NO release and parasite killing. A blockade of LTB4 or PAF receptors partially inhibited IFN-γ-induced NO and TNF-α production but not parasite killing. Finally, daily treatment of infected mice with CP-105,696 was accompanied by a significantly higher level of blood parasitemia, but not lethality, than that seen in vehicle-treated animals. In conclusion, our results suggest a role for LTB4 during experimental T. cruzi infection. Chemoattractant molecules such as LTB4 not only may play a major role in leukocyte migration into sites of inflammation in vivo but also, in the event of an infection, may play a relevant role in the activation of recruited leukocytes to kill the invading microorganism in an NO-dependent manner.

scholarly journals Hepatitis C Virus E1 Protein Enhances Macrophage iNOS Expression In Vitro

2021 ◽  
Author(s):  
Batkhishig Munkhjargal ◽  
Bilguun Enkhtuvshin ◽  
Uranbileg Ulziisaikhan ◽  
Baljinnyam Tuvdenjamts ◽  
Khulan Unurbuyan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Immune Response ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cell Response ◽  
Inos Expression ◽  
No Production ◽  
E1 Protein ◽  
Ifn Γ

AbstractObjectiveHepatitis C virus (HCV) is a single-stranded RNA virus that causes chronic hepatitis, cirrhosis, and liver cancer. Approximately 170 million individuals are infected with HCV worldwide. The pathogenesis of HCV-associated liver injury is thought to be due to the host antiviral immune response, including the T cell response, and excessive production of proinflammatory cytokines, reactive oxygen species, and nitric oxide (NO).Interferon-γ (IFN-γ) is a key cytokine in the adaptive immune response that is primarily secreted from CD4+ T helper cells to induce cytotoxic T lymphocyte (CTL) cell response against HCV infection. Another important role of IFN-γ is the activation of macrophages in the liver resulting in inhibition of viral replication and increased NO production.Enhanced inducible nitric oxide synthase (iNOS) expression and NO production observed in the liver of HCV-infected patients is positively correlated with viral load and hepatic inflammation. HCV-infected macrophages are major producers of NO in the liver. It is not completely understood how HCV proteins affect iNOS expression and what the role of IFN-γ is in HCV protein expression in HCV-infected macrophages. In this study, we examined the effect of INF-γ and HCV proteins on iNOS expression in the Raw264.7 cell line.ResultsConsistent with other studies, HCV core and NS5A proteins induced iNOS expression in macrophages. Moreover, HCV E1 protein-enhanced iNOS expression is highest in the presence and absence of IFN-γ activation.ConclusionThese results indicate that hepatitis C virus core, NS5A, E1 protein regulates iNOS protein expression in IFN-γ-activated and resting macrophage cell lines. These findings points to a future research direction for understanding the pathogenesis of HCV-related liver inflammation.

scholarly journals Characterization of theIn VitroChlamydia pecorumResponse to Gamma Interferon

2018 ◽  
Vol 86 (4) ◽  
Author(s):  
M. Mominul Islam ◽  
Martina Jelocnik ◽  
Wilhelmina M. Huston ◽  
Peter Timms ◽  
Adam Polkinghorne
Keyword(s):  
Immune Response ◽  
Epithelial Cells ◽  
Host Cell ◽  
Anthranilic Acid ◽  
Gamma Interferon ◽  
Tryptophan Depletion ◽  
Content Type ◽  
Natural Hosts ◽  
Ifn Γ

ABSTRACTChlamydia pecorumis an important intracellular bacterium that causes a range of diseases in animals, including a native Australian marsupial, the koala. In humans and animals, a gamma interferon (IFN-γ)-mediated immune response is important for the control of intracellular bacteria. The present study tested the hypotheses thatC. pecorumcan escape IFN-γ-mediated depletion of host cell tryptophan pools. In doing so, we demonstrated that, unlikeChlamydia trachomatis,C. pecorumis completely resistant to IFN-γ in human epithelial cells. While the growth ofC. pecorumwas inhibited in tryptophan-deficient medium, it could be restored by the addition of kynurenine, anthranilic acid, and indole, metabolites that could be exploited by the gene products of theC. pecorumtryptophan biosynthesis operon. We also found that expression oftrpgenes was detectable only whenC. pecorumwas grown in tryptophan-free medium, with gene repression occurring in response to the addition of kynurenine, anthranilic acid, and indole. When grown in bovine kidney epithelial cells, bovine IFN-γ also failed to restrict the growth ofC. pecorum, whileC. trachomatiswas inhibited, suggesting thatC. pecorumcould use the same mechanisms to evade the immune responsein vivoin its natural host. Highlighting the different mechanisms triggered by IFN-γ, however, both species failed to grow in murine McCoy cells treated with murine IFN-γ. This work confirms previous hypotheses about the potential survival ofC. pecorumafter IFN-γ-mediated host cell tryptophan depletion and raises questions about the immune pathways used by the natural hosts ofC. pecorumto control the widespread pathogen.

scholarly journals Human CD46 Enhances Nitric Oxide Production in Mouse Macrophages in Response to Measles Virus Infection in the Presence of Gamma Interferon: Dependence on the CD46 Cytoplasmic Domains

1999 ◽  
Vol 73 (6) ◽  
pp. 4776-4785 ◽  
Author(s):  
Akiko Hirano ◽  
Ziping Yang ◽  
Yuko Katayama ◽  
Jennifer Korte-Sarfaty ◽  
Timothy C. Wong
Keyword(s):  
Nitric Oxide ◽  
Measles Virus ◽  
Cytoplasmic Domain ◽  
Gamma Interferon ◽  
Human Cells ◽  
No Production ◽  
Cytoplasmic Domains ◽  
Juxtamembrane Region ◽  
Mouse Macrophages ◽  
Ifn Γ

ABSTRACT CD46 is a transmembrane complement regulatory protein widely expressed on nucleated human cells. Laboratory-adapted strains of measles virus (MV) bind to the extracellular domains of CD46 to enter human cells. The cytoplasmic portion of CD46 consists of a common juxtamembrane region and different distal sequences called Cyt1 and Cyt2. The biological functions of these cytoplasmic sequences are unknown. In this study, we show that expression of human CD46 with the Cyt1 cytoplasmic domain in mouse macrophages enhances production of nitric oxide (NO) in response to MV infection in the presence of gamma interferon (IFN-γ). Human CD46 does not increase the basal levels of NO production in mouse macrophages and does not augment NO production induced by double-stranded polyribonucleotides. Replacing the cytoplasmic domain of human CD46 with Cyt2 reduces MV and IFN-γ-induced NO production in mouse macrophages. Deleting the entire cytoplasmic domains of human CD46 does not prevent MV infection but markedly attenuates NO production in response to MV and IFN-γ. Mouse macrophages expressing a tailless human CD46 mutant are more susceptible to MV infection and produce 2 to 3 orders of magnitude more infectious virus than mouse macrophages expressing human CD46 with intact cytoplasmic domains. These results reveal a novel function of CD46 dependent on the cytoplasmic domains (especially Cyt1), which augments NO production in macrophages. These findings may have significant implications for roles of CD46 in innate immunity and MV pathogenesis.

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