scholarly journals Gamma Interferon Production Is Critical for Protective Immunity to Infection with Blood-Stage Plasmodium berghei XAT but Neither NO Production nor NK Cell Activation Is Critical

1999 ◽  
Vol 67 (5) ◽  
pp. 2349-2356 ◽  
Author(s):  
Toshihiko Yoneto ◽  
Takayuki Yoshimoto ◽  
Chrong-Reen Wang ◽  
Yasuhiro Takahama ◽  
Moriya Tsuji ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Plasmodium Berghei ◽  
Cell Activation ◽  
Nk Cell ◽  
Gamma Interferon ◽  
No Production ◽  
Wild Type ◽  
Mouse Splenocytes ◽  
Ifn Γ ◽  
Wild Type Control

ABSTRACT We have examined the roles of gamma interferon (IFN-γ), nitric oxide (NO), and natural killer (NK) cells in the host resistance to infection with the blood-stage malarial parasite Plasmodium berghei XAT, an irradiation-induced attenuated variant of the lethal strain P. berghei NK65. Although the infection withP. berghei XAT enhanced NK cell lytic activity of splenocytes, depletion of NK1.1+ cells caused by the treatment of mice with anti-NK1.1 antibody affected neither parasitemia nor IFN-γ production by their splenocytes. The P. bergheiXAT infection induced a large amount of NO production by splenocytes during the first peak of parasitemia, while P. berghei NK65 infection induced a small amount. Unexpectedly, however, mice deficient in inducible nitric oxide synthase (iNOS−/−) clearedP. berghei XAT after two peaks of parasitemia were observed, as occurred for wild-type control mice. Although the infected iNOS−/− mouse splenocytes did not produce a detectable level of NO, they produced an amount of IFN-γ comparable to that produced by wild-type control mouse splenocytes, and treatment of these mice with neutralizing anti-IFN-γ antibody led to the progression of parasitemia and fatal outcome. CD4−/− mice infected withP. berghei XAT could not clear the parasite, and all these mice died with apparently reduced IFN-γ production. Furthermore, treatment with carrageenan increased the susceptibility of mice toP. berghei XAT infection. These results suggest that neither NO production nor NK cell activation is critical for the resistance to P. berghei XAT infection and that IFN-γ plays an important role in the elimination of malarial parasites, possibly by the enhancement of phagocytic activity of macrophages.

scholarly journals Mice Deficient in Interleukin-4 (IL-4) or IL-4 Receptor α Have Higher Resistance to Sporozoite Infection with Plasmodium berghei (ANKA) than Do Naive Wild-Type Mice

2004 ◽  
Vol 72 (1) ◽  
pp. 322-331 ◽  
Author(s):  
Michael Saeftel ◽  
Andreas Krueger ◽  
Sandra Arriens ◽  
Volker Heussler ◽  
Paul Racz ◽  
...  
Keyword(s):  
Nk Cells ◽  
Plasmodium Berghei ◽  
Nk Cell ◽  
Interleukin 4 ◽  
Mouse Strains ◽  
No Production ◽  
Liver Stage ◽  
Innate Immune Mechanism ◽  
Ifn Γ

ABSTRACT BALB/c interleukin-4 (IL-4−/−) or IL-4 receptor-α (IL-4rα−/−) knockout (KO) mice were used to assess the roles of the IL-4 and IL-13 pathways during infections with the blood or liver stages of plasmodium in murine malaria. Intraperitoneal infection with the blood-stage erythrocytes of Plasmodium berghei (ANKA) resulted in 100% mortality within 24 days in BALB/c mice, as well as in the mutant mouse strains. However, when infected intravenously with the sporozoite liver stage, 60 to 80% of IL-4−/− and IL-4rα−/− mice survived, whereas all BALB/c mice succumbed with high parasitemia. Compared to infected BALB/c controls, the surviving KO mice showed increased NK cell numbers and expression of inducible nitric oxide synthase (iNOS) in the liver and were able to eliminate parasites early during infection. In vivo blockade of NO resulted in 100% mortality of sporozoite-infected KO mice. In vivo depletion of NK cells also resulted in 80 to 100% mortality, with a significant reduction in gamma interferon (IFN-γ) production in the liver. These results suggest that IFN-γ-producing NK cells are critical in host resistance against the sporozoite liver stage by inducing NO production, an effective killing effector molecule against Plasmodium. The absence of IL-4-mediated functions increases the protective innate immune mechanism identified above, which results in immunity against P. berghei infection in these mice, with no major role for IL-13.

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 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 Involvement of T Cells in Enhanced Resistance to Klebsiella pneumoniae Septicemia in Mice Treated with Liposome-Encapsulated Muramyl Tripeptide Phosphatidylethanolamine or Gamma Interferon

1998 ◽  
Vol 66 (5) ◽  
pp. 1962-1967 ◽  
Author(s):  
Timo L. M. ten Hagen ◽  
Wim van Vianen ◽  
Huub F. J. Savelkoul ◽  
Hubertine Heremans ◽  
Wim A. Buurman ◽  
...  
Keyword(s):  
T Cells ◽  
Klebsiella Pneumoniae ◽  
Host Defense ◽  
Cell Activation ◽  
Nk Cell ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Th1 Cell ◽  
Cd8 Cells ◽  
Ifn Γ

ABSTRACT We have previously shown that prophylactic administration of the liposome-encapsulated immunomodulating agents muramyl tripeptide phosphatidylethanolamine (MTPPE) and gamma interferon (IFN-γ) results in strongly increased survival of mice from a normally lethal septicemia with Klebsiella pneumoniae. It was anticipated that the treatment acts on macrophages and nonspecifically augments host resistance to various infections. In the present study, we provide evidence for a key role for T cells in host defense potentiation by the liposomal immunomodulators toward K. pneumoniae septicemia. It is shown that both CD4 and CD8 cells are important in immunomodulation, most likely due to production of IFN-γ. Depletion of circulating IFN-γ resulted in strong reduction of the antimicrobial host defense activation. Administration of interleukin-10 resulted in decreased antimicrobial host defense activation by liposomal immunomodulators. Moreover, administration of liposomal immunomodulators was shown to induce predominantly T-helper type 1 (Th1) cell populations in the spleen. These findings indicate that immunomodulation with liposomal MTPPE and IFN-γ favors Th1 and NK cell activation.

scholarly journals Dendritic Cell and NK Cell Reciprocal Cross Talk Promotes Gamma Interferon-Dependent Immunity to Blood-Stage Plasmodium chabaudi AS Infection in Mice

2008 ◽  
Vol 77 (2) ◽  
pp. 770-782 ◽  
Author(s):  
Rebecca Ing ◽  
Mary M. Stevenson
Keyword(s):  
Nk Cells ◽  
Cross Talk ◽  
Cell Activation ◽  
Reciprocal Cross ◽  
Nk Cell ◽  
Gamma Interferon ◽  
Cell Contact ◽  
Ifn Γ ◽  
Dc Maturation

ABSTRACT Dendritic cells (DCs) are important accessory cells for promoting NK cell gamma interferon (IFN-γ) production in vitro in response to Plasmodium falciparum-infected red blood cells (iRBC). We investigated the requirements for reciprocal activation of DCs and NK cells leading to Th1-type innate and adaptive immunity to P. chabaudi AS infection. During the first week of infection, the uptake of iRBC by splenic CD11c+ DCs in resistant wild-type (WT) C57BL/6 mice was similar to that in interleukin 15−/− (IL-15−/−) and IL-12p40−/− mice, which differ in the severity of P. chabaudi AS infection. DCs from infected IL-15−/− mice expressed costimulatory molecules, produced IL-12, and promoted IFN-γ secretion by WT NK cells in vitro as efficiently as WT DCs. In contrast, DCs from infected IL-12p40−/− mice exhibited alterations in maturation and cytokine production and were unable to induce NK cell IFN-γ production. Coculture of DCs and NK cells demonstrated that DC-mediated NK cell activation required IL-12 and, to a lesser extent, IL-2, as well as cell-cell contact. In turn, NK cells from infected WT mice enhanced DC maturation, IL-12 production, and priming of CD4+ T-cell proliferation and IFN-γ secretion. Infected WT mice depleted of NK cells, which exhibit increased parasitemia, had impaired DC maturation and DC-induced CD4+ Th1 cell priming. These findings indicate that DC-NK cell reciprocal cross talk is critical for control and rapid resolution of P. chabaudi AS infection and provide in vivo evidence for the importance of this interaction in IFN-γ-dependent immunity to malaria.

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 NK Cells in Gamma-Interferon-Deficient Mice Suppress Lung Innate Immunity against Mycoplasma spp.

2005 ◽  
Vol 73 (10) ◽  
pp. 6742-6751 ◽  
Author(s):  
Matthew D. Woolard ◽  
Dorothy Hudig ◽  
Leslie Tabor ◽  
James A. Ivey ◽  
Jerry W. Simecka
Keyword(s):  
Innate Immunity ◽  
Nk Cells ◽  
Nk Cell ◽  
Gamma Interferon ◽  
Cell Depletion ◽  
Wild Type ◽  
Negative Effects ◽  
Positive Effects ◽  
Lung Innate Immunity ◽  
Ifn Γ

ABSTRACT The purpose of this study was to examine the 100-fold difference in mycoplasma levels in lungs of gamma interferon knockout (IFN-γ−/−) mice compared to those seen with wild-type BALB/c mice at 3 days postinfection. NK cells secreted IFN-γ; however, their cytotoxic granule extracts failed to kill mycoplasma. We found a conundrum: the clearance of organisms was as effective in NK-depleted IFN-γ−/− animals as in wild-type mice (with both IFN-γ and NK cells). NK+ IFN-γ−/− animals had high mycoplasma burdens, but, after NK-like cell depletion, mycoplasma numbers were controlled. Essentially, IFN-γ was important in animals with NK-like cells and unimportant in animals without NK cells, suggesting that IFN-γ counters deleterious effects of NK-like cells. Impairment of innate immunity in IFN-γ−/− mice was not due to NK-like cell killing of macrophages. The increased levels of inflammatory cytokines and neutrophils in lung fluids of NK+ IFN-γ−/− mice were reduced after NK cell depletion. In summary, in the murine model that resembles chronic human disease, innate immunity to mycoplasma requires IFN-γ when there are NK-like cells and the positive effects of IFN-γ counteract negative effects of NK-like cells. When imbalanced, NK-like cells promote disease. Thus, it was not the lack of IFN-γ but the presence of a previously unrecognized NK-like cell-suppressive activity that contributed to the higher mycoplasma numbers. It appears that pulmonary NK cells may contribute to the immunosuppressive environment of the lung, but when needed, these dampening effects can be counterbalanced by IFN-γ. Furthermore, there may be instances where perturbation of this regulatory balance contributes to the susceptibility to and severity of disease.

Altered Immune Response of Interferon Regulatory Factor 1-Deficient Mice against Plasmodium berghei Blood-Stage Malaria Infection

1999 ◽  
Vol 67 (5) ◽  
pp. 2277-2283 ◽  
Author(s):  
Rosemary Sok-Pin Tan ◽  
Chiguang Feng ◽  
Yoshihiro Asano ◽  
Anna Ursula Kara
Keyword(s):  
Nitric Oxide ◽  
Immune Response ◽  
Plasmodium Berghei ◽  
Interferon Regulatory Factor ◽  
Blood Stage ◽  
Wild Type ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1 ◽  
In The Wild ◽  
Ifn Γ

ABSTRACT Nitric oxide (NO) is a short-lived biological mediator which can be induced in various cell types and is able to cause many metabolic changes in target cells. Inhibition of tumor cell growth and antimicrobial activity has been attributed to the stimulation of NO production by transcriptional upregulation of inducible nitric oxide synthase. In the present study, we used mice devoid of functional interferon regulatory factor 1 by targeted gene disruption (IRF-1−/−) to investigate the role of NO in the host immune response against blood-stage Plasmodium berghei ANKA infection. IRF-1−/− mice survived longer with a later onset of and a lower peak parasitemia despite the inability to produce appreciable levels of NO. The administration of exogenous interleukin-12 (IL-12) was able to prolong survival in the wild-type mice with an upregulation in the expression of both gamma interferon (IFN-γ) and NO. However, the administration of IL-12 did not improve the survival of IRF-1−/− mice. These studies indicate that while IL-12 is able to mediate protection via an IFN-γ- and NO-dependent pathway in the wild-type mice, such a protective mechanism may not be functional in the IRF-1−/− mice. Our results suggest that NO may not be essential for host immunity to the parasite and that IRF-1−/− mice are able to induce an IFN-γ- and NO-independent mechanism against P. berghei infection.

scholarly journals CD1d Mediates T-Cell-Dependent Resistance to Secondary Infection with Encephalomyocarditis Virus (EMCV) In Vitro and Immune Response to EMCV Infection In Vivo

2006 ◽  
Vol 80 (14) ◽  
pp. 7146-7158 ◽  
Author(s):  
Petr O. Ilyinskii ◽  
Ruojie Wang ◽  
Steven P. Balk ◽  
Mark A. Exley
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Activation ◽  
Nk Cell ◽  
Nkt Cells ◽  
Encephalomyocarditis Virus ◽  
Wild Type ◽  
Ifn Γ

ABSTRACT The innate and adaptive immune responses have evolved distinct strategies for controlling different viral pathogens. Encephalomyocarditis virus (EMCV) is a picornavirus that can cause paralysis, diabetes, and myocarditis within days of infection. The optimal innate immune response against EMCV in vivo requires CD1d. Interaction of antigen-presenting cell CD1d with distinct natural killer T-cell (“NKT”) populations can induce rapid gamma interferon (IFN-γ) production and NK-cell activation. The T-cell response of CD1d-deficient mice (lacking all NKT cells) against acute EMCV infection was further studied in vitro and in vivo. EMCV persisted at higher levels in CD1d-knockout (KO) splenocyte cultures infected in vitro. Furthermore, optimal resistance to repeat cycles of EMCV infection in vitro was also shown to depend on CD1d. However, this was not reflected in the relative levels of NK-cell activation but rather by the responses of both CD4+ and CD8+ T-cell populations. Repeated EMCV infection in vitro induced less IFN-γ and alpha interferon (IFN-α) from CD1d-deficient splenocytes than with the wild type. Furthermore, the level of EMCV replication in wild-type splenocytes was markedly and specifically increased by addition of blocking anti-CD1d antibody. Depletion experiments demonstrated that dendritic cells contributed less than the combination of NK and NKT cells to anti-EMCV responses and that none of these cell types was the main source of IFN-α. Finally, EMCV infection in vivo produced higher levels of viremia in CD1d-KO mice than in wild-type animals, coupled with significantly less lymphocyte activation and IFN-α production. These results point to the existence of a previously unrecognized mechanism of rapid CD1d-dependent stimulation of the antiviral adaptive cellular immune response.

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