Type 1 Interferon (IFNα/β) and Type 2 Nitric Oxide Synthase Regulate the Innate Immune Response to a Protozoan Parasite
ImmunityPublished 1 January 1998Open access
Andreas Diefenbach, Heike Schindler, Norbert Donhauser, E Lorenz, Tamás Laskay, John D. MacMicking
Citations370
SJR quartileQ1
SJR score12.16
SNIP4.01
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TL;DR
Type 2 nitric oxide synthase (NOS2) is required for the Th1-dependent healing of infections with intracellular microbes, including Leishmania major, and IFNalpha/beta and NOS2 are critical regulators of the innate response to L. major.
Abstract
Type 2 nitric oxide synthase (NOS2) is required for the Th1-dependent healing of infections with intracellular microbes, including Leishmania major. Here, we demonstrate the expression and define the function of NOS2 during the innate response to L. major. At day 1 of infection, genetic deletion or functional inactivation of NOS2 abolished the IFNgamma and natural killer cell response, increased the expression of TGFbeta, and caused parasite spreading from the skin and lymph node to the spleen, liver, bone marrow, and lung. Induction of NOS2 was dependent on IFNalpha/beta. Neutralization of IFNalpha/beta mimicked the phenotype of NOS2-/- mice. Thus, IFNalpha/beta and NOS2 are critical regulators of the innate response to L. major.
Keywords
Immunology and MicrobiologyMedicineEnvironmental Science
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Although the high-output NO pathway probably evolved to protect the host from infection, suppressive effects on lymphocyte proliferation and damage to other normal host cells confer upon NOS2 the same protective/destructive duality inherent in every other major component of the immune response.
The Journal of ImmunologyRelease of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production.
2,836 Citations1988Aihao Ding, Carl Nathan +1 more
Testing as a sole agent, IFN-gamma was the only one of the 12 cytokines capable of inducing both NO2- and H2O2 release and the pathways leading to secretion of H2 O2 and No2- are independent.
NatureAltered immune responses in mice lacking inducible nitric oxide synthase
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Annual Review of ImmunologyThe Regulation of Immunity to Leishmania Major
1,254 Citations1995Steven L. Reiner, Richard M. Locksley
Use of the murine L. major model continues to elucidate new methods for vaccine development and suggests a promising system for identification of genes that determine susceptibility to infection.
Proceedings of the National Academy of SciencesIdentification of nitric oxide synthase as a protective locus against tuberculosis
1,163 Citations1997John D. MacMicking, R J North +4 more
NOS2(-/-) mice proved highly susceptible, resembling wild-type littermates immunosuppressed by high-dose glucocorticoids, and allowed Mycobacterium tuberculosis to replicate faster in the lungs than reported for other gene-deficient hosts.
The Journal of ImmunologyMacrophage killing of <i>Leishmania</i> parasite in vivo is mediated by nitric oxide from <scp>l</scp> -arginine.
743 Citations1990Foo Y. Liew, S Millott +3 more
No is an effector mechanism in macrophage killing of intracellular protozoa in vivo and the importance of NO in vivo is demonstrated by the finding that CBA mice infected with L. major developed exacerbated disease when L-NMMA was injected into the lesions, resulting in 10(4)-fold increases in the number of parasites extractable from the lesions.
Journal of Biological ChemistryInduction and Stabilization of IκBα by Nitric Oxide Mediates Inhibition of NF-κB
713 Citations1995Haibing Peng, Peter Libby +1 more
It is proposed that the induction and stabilization of I kappa B alpha by NO are important mechanisms by which NO inhibits NF-kappa B and attenuate atherogenesis.
The Journal of Experimental MedicineNatural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice.
608 Citations1993Tanya M. Scharton, Phillip Scott
Data indicate that the stimulation of NK cells, through the production of IFN-gamma, plays an important role in initiating Th1 cell differentiation in leishmaniasis and in controlling early resistance to L. major.
The Journal of ImmunologyEffects of transforming growth factor <i>beta</i> on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness.
568 Citations1986A H Rook, John H. Kehrl +6 more
Results indicate that in addition to inhibitory effects on T and B cells, TGF-beta also inhibits NK cell function.
The Journal of Experimental MedicineRole of interferon regulatory factor 1 in induction of nitric oxide synthase.
480 Citations1994Emil Martin, C F Nathan +1 more
iNOS is identified as the first gene that requires IRF-1 for IFN-gamma-dependent transcriptional regulation, and site-specific substitution of two conserved nucleotides withinIRF-E in the context of the full-length iNOS promoter ablatedIFN- gamma's contribution to synergistic enhancement of transcription.
Journal of Biological ChemistryThe murine transforming growth factor-beta precursor.
475 Citations1986Rik Derynck, Julie A. Jarrett +2 more
Two areas of the precursor exhibit a marked degree of homology to the human counterpart and suggests an important biological function for this area of TGF-beta, which can act, often in cooperation with other growth factors, as a mitogenic factor for a variety of cells.
The Journal of Experimental MedicineInducible Nitric Oxide Is Essential for Host Control of Persistent but Not Acute Infection with the Intracellular Pathogen <i>Toxoplasma gondii</i>
437 Citations1997Tanya Scharton‐Kersten, George Yap +2 more
Early resistance to Toxoplasma gondii infection was ablated by neutralization of IFN-γ or IL-12 in vivo and markedly diminished by depletion of neutrophils, demonstrating the existence of previously unappreciated NO independent mechanisms operating against the parasite during early infection.
The Journal of Experimental MedicineLeishmania promastigotes evade interleukin 12 (IL-12) induction by macrophages and stimulate a broad range of cytokines from CD4+ T cells during initiation of infection.
365 Citations1994Steven L. Reiner, Shichun Zheng +3 more
Interleukin 12 has been recently identified as a macrophage-derived cytokine capable of mediating Th1 effector cell development, and of markedly enhancing interferon gamma (IFN-gamma) production by T cells and natural killer cells, suggesting that IL-2 and IL-13 may mediate the IL-12-independent production of IFN- gamma during the first days after infection.
ImmunityMultistage Regulation of Th1-Type Immune Responses by the Transcription Factor IRF-1
356 Citations1997Shinsuke Taki, Takeo Sato +10 more
It is shown that T cells from mice lacking the transcription factor IRF-1 fail to mount Th1 responses and instead exclusively undergo Th2 differentiation in vitro, indicating the involvement of IRf-1 in multiple stages of the Th1 limb of the immune response.
The Journal of Experimental MedicineReactivation of latent leishmaniasis by inhibition of inducible nitric oxide synthase.
331 Citations1996Steffen Stenger, Norbert Donhauser +3 more
It is concluded that iNOS activity is crucial for the control of Leishmania persisting in immunocompetent hosts after resolution of the primary infection.
ImmunityIL-4 Rapidly Produced by Vβ4 Vα8 CD4+ T Cells Instructs Th2 Development and Susceptibility to Leishmania major in BALB/c Mice
306 Citations1997Pascal Launois, Ivan Maillard +8 more
The IL-4 required for Th2 development and susceptibility to L. major is produced by a restricted population of V beta 4 V alpha 8 CD4+ T cells after cognate interaction with a single antigen from this complex organism.
Immunology TodayThe neglected role of type I interferon in the T-cell response: implications for its clinical use
299 Citations1996Filippo Belardelli, Ion Gresser
Recent experimental results on the interactions of type I IFN with T cells, which may prove important in its use in patients, are summarized.
The Journal of Experimental MedicineTissue expression of inducible nitric oxide synthase is closely associated with resistance to Leishmania major.
298 Citations1994Steffen Stenger, H Thüring +2 more
The pronounced expression of iNOS in resistant mice is an important mechanism for the elimination of Leishmania in vivo and might be a consequence of macrophage deactivation by TGF-beta and reduced responsiveness to IFN-gamma.
ImmunityInterferon Regulatory Factor-1 Is Required for a T Helper 1 Immune Response In Vivo
286 Citations1997Michael Lohoff, David A. Ferrick +5 more
It is shown that CD4+ T cells from Leishmania-infected mice lacking one (+/-) or both (-/-) alleles of the IRF-1 gene developed a profound, gene dose-dependent decrease in IFNgamma production, which is a determining factor for Th1 responses.
The Journal of Experimental MedicineIL-4-deficient Balb/c mice resist infection with Leishmania major.
273 Citations1996Manfred Köpf, Frank Brombacher +7 more
It is suggested that the magnitude of the IL-4 response determines the severity of disease, and that the induction of inflammatory cytokines together with iNOS in the lesion and draining lymph nodes was not altered in the absence of IL- 4.
The Journal of ImmunologyRelease of nitric oxide during the T cell-independent pathway of macrophage activation. Its role in resistance to Listeria monocytogenes
250 Citations1993Karen Beckerman, Howard W. Rogers +4 more
It is concluded that NO. is a critical effector molecule of T cell-independent natural resistance to LM as studied in the SCID mouse, and that the NO.-mediated response is essential for both SCID and immunocompetent host to survive after LM infection.
The EMBO JournalCritical role of a common transcription factor, IRF‐1, in the regulation of IFN‐beta and IFN‐inducible genes.
249 Citations1992Luiz F. L. Reis, Hisashi Harada +3 more
The data show that IRF‐1 is essential for the induced expression of the IFN‐beta gene, and indicate an important role of IRf‐1 in the expression ofIFN‐inducible genes and suggest a role for IRF•1 in many other cytokine actions.
Current Opinion in ImmunologyEffects of IL-12 on immune responses to microbial infections: a key mediator in regulating disease outcome
244 Citations1995Christine A. Biron
Under appropriate conditions, IL-12 has therapeutic efficacy for promoting defense against a variety of pathogens, and for use as a vaccine adjuvant to enhance beneficial Th1 over detrimental Th2 lymphocyte responses.
The FASEB JournalNitric oxide and cGMP analogs activate transcription from AP‐1‐responsive promoters in mammalian cells
189 Citations1995Renate B. Pilza, Modem Suhasini +3 more
Activation of TRE‐regulated genes by NO‐releasing agents and cGMP analogs appeared to be mediated by the AP‐1 (Jun/Fos) transcription factor complex, which was observed to be associated with c‐jun mRNA induction and was not observed with CRE‐containing promoters.
The Journal of ImmunologyNitric oxide signaling: a possible role for G proteins.
171 Citations1993Harry M. Lander, P. K. Sehajpal +1 more
It is found that nitric oxide treatment of membranes isolated from fresh human PBMC enhances the ability of these membranes to hydrolyze GTP and bind GTP, and the GTPase activity of pure, recombinant Gs alpha, Gi alpha 1, and p21ras was greatly enhanced by nitricoxide.
BloodNitric oxide modulation of human leukemia cell differentiation and gene expression
168 Citations1992G Magrinat, S. Nicholas Mason +2 more
NO elaborated in the bone marrow microenvironment may have a role in normal and malignant hematopoietic cell growth and differentiation.
The Journal of ImmunologyEffect of in vivo inhibition of nitric oxide production in murine leishmaniasis.
152 Citations1993Thomas G. Evans, L. Thai +2 more
The results show that cytokine induced NO has a major effector role in resistance of murine hosts to Leishmania infection and leads to a cachectic state not caused by infection alone or inhibition of NO synthesis alone.
Journal of Leukocyte BiologyRegulation of cytokine gene expression by reactive oxygen and reactive nitrogen intermediates
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The data indicate that ROI and RNI can serve as intracellular second messengers to induce IL‐8 gene expression, and the hydroxyl radical appears to be the final common pathway of cell activation forIL‐8 synthesis.
European Journal of ImmunologyEarly parasite containment is decisive for resistance to <i>Leishmania major</i> infection
147 Citations1995Tamás Laskay, Andreas Diefenbach +2 more
The data show that local restriction of parasites in the pre‐T cell phase of the infection is mediated by the innate immune system and suggest that this function plays an important role in the development of a protective T cell response.
European Journal of ImmunologyNitric oxide up‐regulates the release of inflammatory mediators by mouse macrophages
142 Citations1995Janusz Marcinkiewicz, Agnieszka Grabowska +1 more
The results demonstrate that NO can enhance the release of both tumor necrosis factor‐α and interleukin‐1α, and chemiluminescence, and thus can contribute both directly and indirectly to the immunopathology of macrophage‐dependent inflammation.
European Journal of ImmunologyAnalysis of cytokine mRNA levels in interleukin‐4‐transgenic mice by quantitative polymerase chain reaction
137 Citations1992Cornelia Platzer, Günther Richter +5 more
A plasmid was constructed which contains, in tandem array, 5′ and 3′ primer sequences specific for the cytokine genes IL‐1 to IL‐6, tumor necrosis factor (TNF), lymphotoxin (LT), interferon (IFN)‐γ and β‐actin, and the sensitivity of this approach was demonstrated by the capability to detect a twofold difference in IL‐4 mRNA levels.
The Journal of Experimental MedicineThe transcription factor interferon regulatory factor-1 is essential for natural killer cell function in vivo.
134 Citations1996G S Duncan, Hans-Willi Mittrücker +3 more
In this study, the role of the transcriptional activator IFN regulatory factor-1 (IRF-1) in murine NK cell activity was assessed and it was found that IRf-1 is essential for the induction of NK cell-mediated cytotoxicity and for the in vivo effector functions that are mediated by this activity.
Current Opinion in ImmunologyRole of natural killer cells in innate resistance to protozoan infections
116 Citations1997Tanya Scharton‐Kersten, Alan Sher
Natural killer cells are now recognized as major effectors of innate resistance to protozoan parasites, and the principal mechanism by which they control the growth of these pathogens is indirect, involving cytokine production rather than cytolytic activity.
Journal of Immunological MethodsImproved sandwich enzyme-linked immunosorbent assays for transforming growth factor β1
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Improved TGF-beta 1 SELISAs with comparable sensitivities to the above assay are described based on available sources of commercial monoclonal and polyclonal antibodies.
European Journal of ImmunologyNatural killer cells participate in the early defense against Leishmania major infection in mice
105 Citations1993Tamás Laskay, Martin Röllinghoff +1 more
Data show that NK cells are active participants in the non‐specific phase of anti‐leishmanial activity in the control of parasite multiplication early in the course of L. major infection in mice.
OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information)Release of nitric oxide during the T cell-independent pathway of macrophage activation
102 Citations1993Karen Beckerman, Helen Rogers +4 more
European Journal of ImmunologyCytokine interactions in experimental cutaneous leishmaniasis. Interleukin 4 synergizes with interferon‐γ to activate murine macrophages for killing of <i>Leishmania major</i> amastigotes
82 Citations1991Christian Bogdan, Steffen Stenger +2 more
Evidence is presented that the synergistic action of IL 4 and IFN‐γ occurs via an L‐arginine‐dependent killing pathway, and it is concluded that IL 4 provides a strong stimulus for the killing of intracellular L. major AM provided low concentrations of IFN-γ are present.
European Journal of Pharmacologyl-N6-(1-Iminoethyl)-lysine potently inhibits inducible nitric oxide synthase and is superior to NG-monomethyl-arginine in vitro and in vivo
76 Citations1995Steffen Stenger, H Thüring +3 more
It is concluded that L-N6-(1-iminoethyl)-lysine should be used instead of NG-monomethyl-L-arginine for potent suppression of inducible NO-synthase in vitro and in vivo.
The Journal of ImmunologyTransforming growth factor- <i>beta</i> primes macrophages to express inflammatory gene products in response to particulate stimuli by an autocrine/paracrine mechanism.
60 Citations1993Paul W. Noble, Peter M. Henson +4 more
A novel function for TGF-beta is described as a priming agent for macrophage inflammatory gene expression and a mechanism for local amplification of the inflammatory response is suggested.
Cellular ImmunologyInduction of the Nitric Oxide-Synthesizing Pathway in Fresh and Interleukin 2-Cultured Rat Natural Killer Cells
54 Citations1994Maria Grazia Cifone, Claudio Festuccia +6 more
Investigation of whether a NOS pathway exists in fresh or IL-2-activated NK cells and the importance of NO synthesis in their activation and cytotoxic functions concluded that NO generation by NK and LAK cells, determined as nitrite, citrulline, and cGMP synthesis, correlated well with their cytot toxic activities.
The Journal of Experimental MedicineAntibody to mouse interferon alpha/beta abrogates resistance to the multiplication of Friend erythroleukemia cells in the livers of allogeneic mice.
34 Citations1988Ion Gresser, Chantal Maury +4 more
It is shown that Mx+ congenic C57B1/6 mice injected with FLC exhibited a marked increase in the expression of the Mx protein in the liver, spleen, kidney and lung, and this increase was blocked by treatment of mice with antibody to IFN-alpha/beta.
Infection and ImmunityInduction of alpha/beta interferon and gamma interferon in mice infected with Listeria monocytogenes during pregnancy
33 Citations1985Akio Nakane, Tomonori Minagawa +1 more
The bacterial growth in the organs of pregnant mice in the early stage of infection was normal, but resulted in the delay of T-cell-dependent elimination of bacteria from the organ of pregnant animals in the late stage, and numerous bacteria were detected in both the placenta and the fetus.
PubMedCytokine interactions in experimental cutaneous leishmaniasis.
28 Citations1991Werner Solbach, Martin Röllinghoff +2 more
It is concluded that macrophage activation for antiparasitic activity is directed by a complex network of cytokine-interactions, in which IL-4 and TNF-alpha very effectively synergize positively with low levels of IFN-gamma.
The Journal of Infectious DiseasesListeria monocytogenes-Induced Interferon-v Primes the Host for Production of Tumor Necrosis Factor and Interferon- /
24 Citations1993Edward A. Havell
Antibody-mediated depletion of various cell types in vivo revealed that CD8+ cells and NK cells are required for the production of L. monocytogenes-induced IFN-gamma during the first day of listeriosis.
Cellular ImmunologyGeneration of Lymphokine-Activated Killer Activity in Rodents but Not in Humans Is Nitric Oxide Dependent
20 Citations1994Antonio Juretić, Giulio C. Spagnoli +7 more
The results suggest that LAK cell precursors depend on a exogenous NO supply from other cell types in order to display their full cytotoxic potential.
Journal of VirologyInterferon structural genes do not participate in quantitative regulation of interferon production by If loci as shown in C57BL/6 mice that are congenic with BALB/c mice at the alpha interferon gene cluster
16 Citations1986Jaqueline De Maeyer‐Guignard, F Dandoy +2 more
These mice, carrying the BALB/c IFN-alpha structural genes on a C57BL/6 background, are high IFN producers when stimulated by Newcastle disease virus, Sendai virus, herpes simplex virus type 1, or polyriboinosinic-polyribocytidylic acid.