Cytokine-Induced Synthesis of Nitrogen Oxides in Macrophages: A Protective Host Response to <i>Leishmania</i> and Other Intracellular Pathogens

Green, Shawn J.; Nacy, Carol A.; Meltzer, Monte S.

doi:10.1002/jlb.50.1.93

Cited by 253 publications

(138 citation statements)

References 80 publications

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“…Nitrite measurements. Nitrite concentrations in supernatants from macrophages were determined by use of Griess reagent (1% sulfanilamide in 2.5% phosphoric acid-0.1% n-1-napthylethylenediamide dichlorique [14]). After a 30-min incubation at room temperature with agitation, the absorbance at 540 nm was measured.…”

Section: Methodsmentioning

confidence: 99%

Toll-Like Receptor 2 Is Required for Optimal Control ofListeria monocytogenesInfection

et al. 2004

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The control of Listeria monocytogenes infection depends on the rapid activation of the innate immune system, likely through Toll-like receptors (TLR), since mice deficient for the common adapter protein of TLR signaling, myeloid differentiation factor 88 (MyD88), succumb to Listeria infection. In order to test whether TLR2 is involved in the control of infections, we compared the host response in TLR2-deficient mice with that in wild-type mice. Here we show that TLR2-deficient mice are more susceptible to systemic infection by Listeria than are wild-type mice, with a reduced survival rate, increased bacterial burden in the liver, and abundant and larger hepatic microabscesses containing increased numbers of neutrophils. The production of tumor necrosis factor, interleukin-12, and nitric oxide and the expression of the costimulatory molecules CD40 and CD86, which are necessary for the control of infection, were reduced in TLR2-deficient macrophages and dendritic cells stimulated by Listeria and were almost abolished in the absence of MyD88, coincident with the high susceptibility of MyD88-deficient mice to in vivo infection. Therefore, the present data demonstrate a role for TLR2 in the control of Listeria infection, but other MyD88-dependent signals may contribute to host resistance.

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Section: Methodsmentioning

confidence: 99%

Toll-Like Receptor 2 Is Required for Optimal Control ofListeria monocytogenesInfection

et al. 2004

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“…In a two-step process, iNOS oxidizes L-arginine into NO and NO promotes parasite killing [5,41]. Arginase catalyzes the hydrolysis of L-arginine to urea and L-ornithine.…”

Section: Impaired Ifn-c-induced No Synthesis Inos Expression and Tnfmentioning

confidence: 99%

Effective clearance of intracellular Leishmania majorin vivo requires Pten in macrophages

et al. 2008

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Leishmaniases are a major international public health problem, and macrophages are crucial for host resistance to this parasite. To determine if phosphatase and tensin homologue deleted on chromosome ten (Pten), a negative regulator of the PI3K pathway, plays a role in macrophage-mediated resistance to Leishmania, we generated C57BL/6 mice lacking Pten specifically in macrophages (LysMCrePten flox/flox mice). Examination of lesions resulting from Leishmania major infection showed that LysMCrePten flox/flox mice were more susceptible to the parasite than wild-type (WT) mice in the early phase of the infection, but were eventually able to eliminate the pathogen. In vitro Pten-deficient macrophages showed a reduced ability to kill parasites in response to IFN-c treatment, possibly because the mutant cells exhibited decreased TNF secretion that correlated with reductions in inducible nitric oxide synthase expression and nitric oxide production. In response to various TLR ligands, Pten-deficient macrophages produced less TNF and IL-12 but more IL-10 than WT cells. However, analysis of cells in the lymph nodes draining L. major inoculation sites indicated that both LysMCrePten flox/flox and WT mice developed normal Th1 responses following L. major infection, in line with the ability of LysMCrePten flox/flox mice to eventually eliminate the parasite. Our results indicate that the efficient clearance of intracellular parasites requires Pten in macrophages.Key words: Leishmania Á Macrophage Á Pten IntroductionIn humans, Leishmania infections are classified as self-healing, cutaneous, mucocutaneous or visceral [1]. These clinical manifestations of the disease reflect differences among infecting parasite species as well as the efficiency of the host's immune response to a given species. Many of the clinical manifestations of human leishmaniasis are mimicked in inbred mice, and experimental infection of various mouse strains with Leishmania major is widely used to study resistance and susceptibility to leishmaniasis. These studies have shown that intact phagocyte function is essential for recovery from Leishmania infections. In an attempt to thwart this means of host defense, Leishmania disrupt numerous Eur. J. Immunol. 2008. 38: 1331-1340 Immunity to infection , and this TNF synergizes with IFN-c to promote parasite killing [4, 5]. Mice resistant to infection with L. major have elevated levels of TNF in their draining lymph nodes (LN) during the course of the infection, whereas no TNF is detectable in susceptible animals [6]. In addition, C57BL/6 mice, which are resistant to L. major infection, become susceptible if they transgenically express high levels of the competitive inhibitor soluble hTNFRp55 fusion protein [7]. Knockout mice lacking TNFRp55 or TNF are also susceptible to this parasite [8][9][10].Signaling through both FccR [11] and TLR (especially TLR2 [12] and TLR4 [13, 14]) is known to be important for macrophagemediated defense against Leishmania. However, how these receptors are linked to TNF production is ...

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“…Macrophages were exposed to one amastigote:one macrophage for 2 h at 37 C in polypropylene tubes containing 5 x lO' cells, then treated with IFN--f. After 72 h incubation the percentage of macrophages with intracellular amastigotes was determined from smears made by cytocentrifugation and stained with Leukostat stain (Fisher, Pittsburg, PA). NOi production was measured in culture supernatants by the Greiss reaction [19]. NaNO2 was used as a standard for comparison.…”

Section: Intracellular Killing and Noj Measurementsmentioning

confidence: 99%

Response ofscidmice to establishment ofLeishmania majorinfection

Guy

Belosevic

1995

Clinical and Experimental Immunology

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SUMMARYThe initiation o^ Leishmania major \n^e:c\\ox\ in su.sceptible BALB/c mice is regulated by inlerferongamma (lKN-->). To examine further the mechanisms of lFN-7-dependent regulation of the establishment of L. major, we studied the characteristics of the infection in severe combined immunodeticient {scid) mice. In the lirst 2 weeks of infection, we observed a delay in the development of the lesions in the footpads and lower numbers of parasites in scid compared with BALB/c mice. By week 5 after infection, the size ofthe leishmanial lesion was similar in both strains of mice, but the number of parasites in scid mice was 100-fold higher than in BALB/c. Treatment with anti-IFN-7 during the establishment of L. major did not alter the course of infection in .Wi^mice, while it exacerbated lesion development in BALB/c mice. Macrophages from scid mice were unable to kill L. major when stimulated with IFN--) in vitro, and produced lower levels of nitric oxide compared with macrophages from susceptible BALB/c or the resistant C57B1/ 6 mice. We examined whether delayed lesion development in.«((/mice was due to their inability to mouni appropriate inflammatory responses. While significantly fewer nucleated cells were present in the footpads of .vc/J mice compared with BALB/c. 2 and 3 weeks alter infection, no difference in inflammatory response between scid and BALB/c mice was observed in response to L. major antigen in the footpads. In contrast, there was a dramatic increase in the number ofcells in ihe popliteal lymph nodes of BALB/c mice. Decreased inflammatory responses oWscid mice in Ihe footpad (at (he site of infection) may contribute to slower development of leishmanial lesions during the first 2 weeks of infection.

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Cytokine-Induced Synthesis of Nitrogen Oxides in Macrophages: A Protective Host Response to Leishmania and Other Intracellular Pathogens

Cited by 253 publications

References 80 publications

Toll-Like Receptor 2 Is Required for Optimal Control ofListeria monocytogenesInfection

Toll-Like Receptor 2 Is Required for Optimal Control ofListeria monocytogenesInfection

Effective clearance of intracellular Leishmania majorin vivo requires Pten in macrophages

Response ofscidmice to establishment ofLeishmania majorinfection

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