scholarly journals The Inhibition of Arginase by Nω-Hydroxy-l-Arginine Controls the Growth of Leishmania Inside Macrophages

2001 ◽  
Vol 193 (6) ◽  
pp. 777-784 ◽  
Author(s):  
Virginia Iniesta ◽  
L. Carlos Gómez-Nieto ◽  
Inés Corraliza
Keyword(s):  
Nitric Oxide ◽  
Leishmania Major ◽  
Interleukin 4 ◽  
Leishmania Infection ◽  
Mouse Strains ◽  
Helper Cell Type ◽  
Infected Cells ◽  
Ifn Γ ◽  
Oxide Synthase ◽  
Arginase I

Polyamine synthesis from l-ornithine is essential for Leishmania growth. We have investigated the dependence of Leishmania infection on arginase, which generates l-ornithine, in macrophages from BALB/c, C57BL/6, and nitric oxide synthase II (NOS II)-deficient mouse strains. We have found that Nω-hydroxy-l-arginine (LOHA), a physiological inhibitor of arginase, controls cellular infection and also specifically inhibits arginase activity from Leishmania major and Leishmania infantum parasites. The effect was proportional to the course of infection, concentration dependent up to 100 μM, and achieved without an increase in nitrite levels of culture supernatants. Moreover, when the l-arginine metabolism of macrophages is diverted towards ornithine generation by interleukin 4–induced arginase I, parasite growth is promoted. This effect can be reversed by LOHA. Inhibition of NOS II by NG-methyl-l-arginine (LNMMA) restores the killing obtained in the presence of interferon (IFN)-γ plus lipolysaccharide (LPS), whereas the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5,-tetramethylimidazoline-3-oxide-1-oxyl (carboxy-PTIO) was without effect. However, exogenous l-ornithine almost completely inhibits parasite killing when added in the presence of LOHA to macrophages from NOS II–deficient mice or to BALB/c-infected cells activated with IFN-γ plus LPS. These results suggest that LOHA is an effector molecule involved in the control of Leishmania infection. In addition, macrophage arginase I induction by T helper cell type 2 cytokines could be a mechanism used by parasites to spread inside the host.

scholarly journals Interleukin-4-Independent Acceleration of Cutaneous Leishmaniasis in Susceptible BALB/c Mice following Treatment with Anti-CTLA4 Antibody

1999 ◽  
Vol 67 (12) ◽  
pp. 6454-6460 ◽  
Author(s):  
Frederick P. Heinzel ◽  
Richard A. Maier
Keyword(s):  
Nitric Oxide ◽  
Leishmania Major ◽  
Interleukin 4 ◽  
Treatment Result ◽  
Inos Mrna ◽  
Lymph Node Cells ◽  
Ifn Γ ◽  
Th2 Development ◽  
Oxide Synthase

ABSTRACT BALB/c mice are susceptible to progressive infection withLeishmania major due to the preferential development of CD4+ T cells that secrete Th2 cytokines. Although Th2 cell development and susceptibility are disrupted by blockade of CD86 function early in infection, CD28-deficient BALB/c mice remain susceptible to leishmaniasis. We therefore examined whether the alternative CD86 ligand, CTLA4, contributes to the expression of susceptibility. BALB/c mice treated for 2 weeks of infection with anti-CTLA4 monoclonal antibody developed more rapidly progressive disease than sham-treated mice, whereas normally resistant C57BL/6 mice were unaffected. The draining lymph node cells of anti-CTLA4-treated BALB/c mice produced up to sixfold more interleukin-4 (IL-4) and IL-13 than control mice in the first 2 weeks of infection, but IFN-γ synthesis was reciprocally decreased. Anti-CTLA4 treatment of BALB/c mice pretreated with neutralizing anti-IL-4 antibody or genetically deficient in IL-4 also caused significant worsening of leishmaniasis. Exacerbation in IL-4 KO mice was associated with increased IL-13 and decreased gamma interferon (IFN-γ) and inducible nitric oxide synthase (iNOS) mRNA expression in vivo. These data indicate that anti-CTLA4 antibody induced earlier and more-polarized Th2 responses in susceptible BALB/c mice infected with L. major. The mechanism of disease worsening was partially IL-4 independent, indicating that increased IL-13 and/or decreased IFN-γ production may have disrupted nitric oxide-based microbicidal responses. We conclude that CTLA4 significantly modulates Th2 development in murine leishmaniasis and that the Th2-polarizing effects of anti-CTLA4 treatment result in IL-4-independent exacerbation of disease.

scholarly journals Arginase I Induction during Leishmania major Infection Mediates the Development of Disease

2005 ◽  
Vol 73 (9) ◽  
pp. 6085-6090 ◽  
Author(s):  
Virginia Iniesta ◽  
Jesualdo Carcelén ◽  
Isabel Molano ◽  
Pablo M. V. Peixoto ◽  
Eloy Redondo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Mouse Model ◽  
Differential Expression ◽  
Leishmania Major ◽  
Interleukin 4 ◽  
Major Infection ◽  
Time Of Infection ◽  
Oxide Synthase ◽  
Arginase I

ABSTRACT In a previous work, we demonstrated that the induction of arginase I favored the replication of Leishmania inside macrophages. Now we have analyzed the differential expression of this enzyme in the mouse model of L. major infection. Ours results show that arginase I is induced in both susceptible and resistant mice during the development of the disease. However, in BALB/c-infected tissues, the induction of this protein parallels the time of infection, while in C57BL/6 mice, the enzyme is upregulated only during footpad swelling. The induction of the host arginase in both strains is mediated by the balance between interleukin-4 (IL-4) and IL-12 and opposite to nitric oxide synthase II expression. Moreover, inhibition of arginase reduces the number of parasites and delays disease outcome in BALB/c mice, while treatment with l-ornithine increases the susceptibility of C57BL/6 mice. Therefore, arginase I induction could be considered a marker of disease in leishmaniasis.

scholarly journals Both the Fas Ligand and Inducible Nitric Oxide Synthase Are Needed for Control of Parasite Replication within Lesions in Mice Infected with Leishmania major whereas the Contribution of Tumor Necrosis Factor Is Minimal

2003 ◽  
Vol 71 (9) ◽  
pp. 5287-5295 ◽  
Author(s):  
Reza Chakour ◽  
Reto Guler ◽  
Mélanie Bugnon ◽  
Cindy Allenbach ◽  
Irène Garcia ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Fas Ligand ◽  
Leishmania Major ◽  
Parasite Replication ◽  
Ifn Γ ◽  
Oxide Synthase ◽  
Necrosis Factor ◽  
Inducible Nitric Oxide

ABSTRACT Following infection with the protozoan parasite Leishmania major, C57BL/6 mice develop a small lesion that heals spontaneously. Resistance to infection is associated with the development of CD4+ Th1 cells producing gamma interferon (IFN-γ) and tumor necrosis factor (TNF), which synergize in activating macrophages to their microbicidal state. We show here that C57BL/6 mice lacking both TNF and Fas ligand (FasL) (gld TNF−/− mice) infected with L. major neither resolved their lesions nor controlled Leishmania replication despite the development of a strong Th1 response. Comparable inducible nitric oxide synthase (iNOS) activities were detected in lesions of TNF−/−, gld TNF−/−, and gld mice, but only gld and gld TNF−/− mice failed to control parasite replication. Parasite numbers were high in gld mice and even more elevated in gld TNF−/− mice, suggesting that, in addition to iNOS, the Fas/FasL pathway is required for successful control of parasite replication and that TNF contributes only a small part to this process. Furthermore, FasL was shown to synergize with IFN-γ for the induction of leishmanicidal activity within macrophages infected with L. major in vitro. Interestingly, TNF−/− mice maintained large lesion size throughout infection, despite being able to largely control parasite numbers. Thus, IFN-γ, FasL, and iNOS appear to be essential for the complete control of parasite replication, while the contribution of TNF is more important in controlling inflammation at the site of parasite inoculation.

scholarly journals Defective Nitric Oxide Effector Functions Lead to Extreme Susceptibility of Trypanosoma cruzi-Infected Mice Deficient in Gamma Interferon Receptor or Inducible Nitric Oxide Synthase

1998 ◽  
Vol 66 (3) ◽  
pp. 1208-1215 ◽  
Author(s):  
Christoph Hölscher ◽  
Gabriele Köhler ◽  
Uwe Müller ◽  
Horst Mossmann ◽  
Günter A. Schaub ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Specific Antibody ◽  
Mutant Mouse ◽  
Antibody Responses ◽  
Mouse Strains ◽  
Ifn Γ ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

ABSTRACT Trypanosoma cruzi, the causative agent of Chagas’ disease, induces an innate and adaptive host immune response during the acute phase of infection. These responses were analyzed by comparing mouse lines deficient for the gamma interferon (IFN-γ) receptor (IFN-γR−/−) or deficient for inducible nitric oxide synthase (iNOS−/−). Both lines were highly susceptible, with similar and dramatically increased parasite burdens and severe histopathology and were incapable of surviving even very low doses, exhibiting similar mortality kinetics. This pathophysiological correlation has a common cause, since both mutant mouse strains were unable to respond to infection by producing nitric oxide (NO) with the consequence that mutant macrophages had impaired trypanocidal activities. These in vivo and subsequent in vitro studies further demonstrated that an IFN-γ-dependent pathway of iNOS induction is crucial for efficient NO production and mandatory for resisting acute infection with T. cruzi. Despite this defect, both mutant mouse strains had a rather normal proinflammatory cytokine response (interleukin-12 [IL-12], IFN-γ, IL-6), with the exception of an impaired tumor necrosis factor alpha and IL-1α response in IFN-γR−/− mice, demonstrating that only the latter two cytokines are dependent on IFN-γ activation. Moreover, polarization of T cells in type 1 and type 2 T-helper (Th1/Th2) and cytotoxic T (Tc1/Tc2) cells as well as T. cruzi-specific antibody responses were normal in IFN-γR−/− mice, demonstrating that IFN-γ is not necessary for the promotion of T-cell differentiation and T. cruzi-specific antibody responses.

scholarly journals Interleukin-4 stimulates cGMP production by IFN-gamma-activated human monocytes. Involvement of the nitric oxide synthase pathway

1994 ◽  
Vol 269 (13) ◽  
pp. 9811-9816
Author(s):  
J.P. Kolb ◽  
N. Paul-Eugene ◽  
C. Damais ◽  
K. Yamaoka ◽  
J.C. Drapier ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Interleukin 4 ◽  
Human Monocytes ◽  
Ifn Gamma ◽  
Cgmp Production ◽  
Oxide Synthase

scholarly journals Inducible Nitric Oxide Synthase Is Not Essential for Control of Trypanosoma cruzi Infection in Mice

2004 ◽  
Vol 72 (7) ◽  
pp. 4081-4089 ◽  
Author(s):  
Kara L. Cummings ◽  
Rick L. Tarleton
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Trypanosoma Cruzi ◽  
Inducible Nitric Oxide Synthase ◽  
Interleukin 1 ◽  
Mouse Strains ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

ABSTRACT Immune control of many intracellular pathogens, including Trypanosoma cruzi, is reported to be dependent on the production of nitric oxide. In this study, we show that mice deficient in inducible nitric oxide synthase (iNOS or NOS2) exhibit resistance to T. cruzi infection that is comparable to that of wild-type mice. This is the case for two iNOS-deficient mouse strains, Nos2tm1Lau and Nos2 N5, infected with the Brazil or Tulahuen strain of T. cruzi. In all cases, blood parasitemia, tissue parasite load, and survival rates are similar between wild-type and iNOS-deficient mice. In contrast, both wild-type and Nos2tm1Lau mice died within 32 days postinfection when treated with the nitric oxide synthase inhibitor aminoguanidine. Increased transcription of NOS1 or NOS3 is not found in iNOS-knockout (KO) mice, indicating that the absence of nitric oxide production through iNOS is not compensated for by increased production of other NOS isoforms. However, Nos2tm1Lau mice exhibit enhanced expression of tumor necrosis factor alpha, interleukin-1, and macrophage inflammatory protein 1α compared to that of wild-type mice, and these alterations may in part compensate for the lack of iNOS. These results clearly show that iNOS is not required for control of T. cruzi infection in mice.

scholarly journals Expression of the Nitric Oxide Synthase 2 Gene Is Not Essential for Early Control of Mycobacterium tuberculosis in the Murine Lung

2000 ◽  
Vol 68 (12) ◽  
pp. 6879-6882 ◽  
Author(s):  
Andrea M. Cooper ◽  
John E. Pearl ◽  
Jason V. Brooks ◽  
Stefan Ehlers ◽  
Ian M. Orme
Keyword(s):  
Nitric Oxide ◽  
Mycobacterium Tuberculosis ◽  
Nitric Oxide Synthase ◽  
Low Dose ◽  
Interleukin 12 ◽  
Infection Model ◽  
Rapid Progression ◽  
Ifn Γ ◽  
Nitric Oxide Synthase 2 ◽  
Oxide Synthase

ABSTRACT The interleukin-12 and gamma interferon (IFN-γ) pathway of macrophage activation plays a pivotal role in controlling tuberculosis. In the murine model, the generation of supplementary nitric oxide by the induction of the nitric oxide synthase 2 (NOS2) gene product is considered the principal antimicrobial mechanism of IFN-γ-activated macrophages. Using a low-dose aerosol-mediated infection model in the mouse, we have investigated the role of nitric oxide in controllingMycobacterium tuberculosis in the lung. In contrast to the consequences of a systemic infection, a low dose of bacteria introduced directly into the lungs of mice lacking the NOS2 gene is controlled almost as well as in intact animals. This is in contrast to the rapid progression of disease in mice lacking IFN-γ or a key member of the IFN signaling pathway, interferon regulatory factor 1. Thus while IFN-γ is pivotal in early control of bacterial growth in the lung, this control does not completely depend upon the expression of the NOS2 gene. The absence of inducible nitric oxide in the lung does, however, result in increased polymorphonuclear cell involvement and eventual necrosis in the pulmonary granulomas of the infected mice lacking the NOS2 gene.

Effect of Ninjin-Youei-To on Th1/Th2 Type Cytokine Production in Different Mouse Strains

2002 ◽  
Vol 30 (02n03) ◽  
pp. 215-223 ◽  
Author(s):  
Tsutomu Nakada ◽  
Kenji Watanabe ◽  
Guang-Bi Jin ◽  
Kazuo Toriizuka ◽  
Toshihiko Hanawa
Keyword(s):  
Oral Administration ◽  
Cytokine Production ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Mouse Strains ◽  
Enzyme Linked Immunosorbent Assay ◽  
Herbal Formula ◽  
Beneficial Effects ◽  
Ifn Γ ◽  
Th1 And Th2

Ninjin-Youei-To (NYT; Ren-Shen-Yang-Rong-Tang in Chinese) is a traditional herbal formula, which is widely used in Japan, Korea and China to modulate physiological immunity. The effects of oral administration of NYT on cytokine production from splenocytes were investigated in both C57BL/6 and BALB/c mice in which Th1 and Th2 were dominant, respectively. Splenocytes from C57BL/6 and BALB/c mice, which took NYT orally for four weeks, were cultured with anti-mouse CD3 mAb, and the supernatant was examined for cytokine production using enzyme-linked immunosorbent assay (ELISA). Administration of NYT to C57BL/6 mice, increased the production of interleukin-4 (IL-4) significantly, and slightly decreased interferon-γ (IFN-γ) production from splenocytes. In contrast, the same treatment significantly increased IFN-γ secretion from splenocytes of BALB/c mice. No remarkable changes of IL-12 production from splenocytes were observed in either strain of mice. These results suggest that oral administration of NYT ameliorates the excessive inclination of Th1 and Th2 type cytokine production, and NYT may provide a beneficial effects for the treatment of diseases caused by a skewed Th1-Th2 balance in the immune system.

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