scholarly journals In Vivo Regulation of Replicative Legionella pneumophila Lung Infection by Endogenous Interleukin-12

1998 ◽  
Vol 66 (1) ◽  
pp. 65-69 ◽  
Author(s):  
J. K. Brieland ◽  
D. G. Remick ◽  
M. L. LeGendre ◽  
N. C. Engleberg ◽  
J. C. Fantone
Keyword(s):  
Legionella Pneumophila ◽  
Lung Infection ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Protein Levels ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ

ABSTRACT The in vivo role of endogenous interleukin 12 (IL-12) in modulating intrapulmonary growth of Legionella pneumophila was assessed by using a murine model of replicative L. pneumophila lung infection. Intratracheal inoculation of A/J mice with virulent bacteria (106 L. pneumophilacells per mouse) resulted in induction of IL-12, which preceded clearance of the bacteria from the lung. Inhibition of endogenous IL-12 activity, via administration of IL-12 neutralizing antiserum, resulted in enhanced intrapulmonary growth of the bacteria within 5 days postinfection (compared to untreated L. pneumophila-infected mice). Because IL-12 has previously been shown to modulate the expression of cytokines, including gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and IL-10, which regulate L. pneumophila growth, immunomodulatory effects of endogenous IL-12 on intrapulmonary levels of these cytokines during replicative L. pneumophila lung infection were subsequently assessed. Results of these experiments demonstrated that TNF-α activity was significantly lower, while protein levels of IFN-γ and IL-10 in the lung were similar, in L. pneumophila-infected mice administered IL-12 antiserum, compared to similarly infected untreated mice. Together, these results demonstrate that IL-12 is critical for resolution of replicativeL. pneumophila lung infection and suggest that regulation of intrapulmonary growth of L. pneumophila by endogenous IL-12 is mediated, at least in part, by TNF-α.

scholarly journals Toll-Like Receptor 9 Is Required for Full Host Resistance toMycobacteriumaviumInfection but Plays No Role in Induction of Th1 Responses

2011 ◽  
Vol 79 (4) ◽  
pp. 1638-1646 ◽  
Author(s):  
Natália B. Carvalho ◽  
Fernanda S. Oliveira ◽  
Fernanda V. Durães ◽  
Leonardo A. de Almeida ◽  
Manuela Flórido ◽  
...  
Keyword(s):  
Interleukin 12 ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Histocompatibility Complex ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Myd88 Signaling ◽  
Necrosis Factor

ABSTRACTTo investigate the role of Toll-like receptor 9 (TLR9) in innate immunity toMycobacteriumavium, TLR9, TLR2, and MyD88 knockout (KO) mice were infected with this bacterium. Bacterial burdens were higher in the spleens, livers, and lungs of infected TLR9 KO mice than in those of C57BL/6 mice, indicating that TLR9 is required for efficient control ofM.aviuminfection. However, TLR9 KO or TLR2 KO spleen cells displayed normalM.avium-induced tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) responses. This finding was confirmed by determining the number of splenic CD4+T cells producing IFN-γ by flow cytometry. Furthermore, TLR2 and MyD88, but not TLR9, played a major role in interleukin-12 and TNF-α production byM.avium-infected macrophages and dendritic cells (DCs). We also found that major histocompatibility complex class II molecule expression on DCs is regulated by TLR2 and MyD88 signaling but not by TLR9. Finally, lack of TLR9, TLR2, or MyD88 reduced the numbers of macrophages, epithelioid cells, and lymphocytes inM.avium-induced granulomas but only MyD88 deficiency affected the number of liver granulomas. In summary, our data demonstrated that the involvement of TLR9 in the control ofM.aviuminfection is not related to the induction of Th1 responses.

scholarly journals Protection against Intestinal Amebiasis by a Recombinant Vaccine Is Transferable by T Cells and Mediated by Gamma Interferon

2009 ◽  
Vol 77 (9) ◽  
pp. 3909-3918 ◽  
Author(s):  
Xiaoti Guo ◽  
Lisa Barroso ◽  
Steven M. Becker ◽  
David M. Lyerly ◽  
Thomas S. Vedvick ◽  
...  
Keyword(s):  
T Cells ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Vaccine Protection ◽  
Adjuvant System ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Intestinal Amebiasis

ABSTRACT We have previously shown that vaccination with purified Entamoeba histolytica Gal/GalNAc lectin or recombinant subunits can protect mice from intestinal amebiasis upon intracecal challenge. In this study, we demonstrated with adoptive-transfer experiments that this lectin vaccine protection is mediated by T cells but not serum. The cell-mediated immune (CMI) response was characterized by significant gamma interferon (IFN-γ), interleukin 12 (IL-12), IL-2, IL-10, and IL-17 production. To move toward a human vaccine, we switched to a recombinant protein and tested a range of adjuvants and routes appropriate for humans. We found that subcutaneous delivery of LecA with IDRI's adjuvant system EM014 elicited a potent Th1-type CMI profile and provided significant protection, as measured by culture negativity (79% efficacy); intranasal immunization with cholera toxin provided 56% efficacy; and alum induced a Th2-type response that protected 62 to 68% of mice. Several antibody and CMI cytokine responses were examined for correlates of protection, and prechallenge IFN-γ+ or IFN-γ-, IL-2-, and tumor necrosis factor alpha-triple-positive CD4 cells in blood were statistically associated with protection. To test the role of IFN-γ in LecA-mediated protection, we neutralized IFN-γ in LecA-immunized mice and found that it abrogated the protection conferred by vaccination. These data demonstrate that CMI is sufficient for vaccine protection from intestinal amebiasis and reveal an important role for IFN-γ, even in the setting of alum.

scholarly journals Induction of Interleukin-12 and Gamma Interferon Requires Tumor Necrosis Factor Alpha for Protective T1-Cell-Mediated Immunity to Pulmonary Cryptococcus neoformans Infection

2002 ◽  
Vol 70 (6) ◽  
pp. 2959-2964 ◽  
Author(s):  
Amy C. Herring ◽  
John Lee ◽  
Roderick A. McDonald ◽  
Galen B. Toews ◽  
Gary B. Huffnagle
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Interleukin 12 ◽  
Cell Mediated Immunity ◽  
Pulmonary Eosinophilia ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Necrosis Factor

ABSTRACT The development of T1-cell-mediated immunity is required to clear a pulmonary Cryptococcus neoformans infection. The objective of these studies was to determine the mechanism by which tumor necrosis factor alpha (TNF-α) augments the development of pulmonary T1 immunity to C. neoformans infection. TNF-α expression was detected in lavage sample cells at days 2, 3, and 7 following C. neoformans infection. The numbers of CFU in the lung were not different between control and anti-TNF-α-treated mice at any time point examined during the afferent phase of the response (days 0 to 7). However, neutralization of TNF-α prevented the initiation of pulmonary clearance during the efferent phase of the response (day 14). Administration of anti-TNF-α monoclonal antibody (day 0) diminished the lung levels of TNF-α, interleukin-12 (IL-12), and gamma interferon (IFN-γ) induced by C. neoformans at day 7 postinfection. Neutralization of TNF-α (day 0) also altered the IFN-γ/IL-4 ratio in the lung-associated lymph nodes at day 7 following C. neoformans infection. Anti-TNF-α-treated mice developed a pulmonary eosinophilia at day 14 postinfection. Consistent with the pulmonary eosinophilia, anti-TNF-α-treated mice exhibited elevated serum immunoglobulin E and inhibition of the anticryptococcal delayed-type hypersensitivity response, indicating a shift toward a T2 response. Neutralization of IL-12 also prevented lung leukocyte production of IFN-γ in response to the infection. These findings demonstrate that afferent-phase TNF-α production is essential for the induction of IL-12 and IFN-γ and neutralization of early TNF-α results in a T2 shift of the T1/T2 balance of antifungal immunity.

scholarly journals Immunomodulatory Role of Endogenous Interleukin-18 in Gamma Interferon-Mediated Resolution of Replicative Legionella pneumophila Lung Infection

2000 ◽  
Vol 68 (12) ◽  
pp. 6567-6573 ◽  
Author(s):  
Joan K. Brieland ◽  
Craig Jackson ◽  
Steve Hurst ◽  
David Loebenberg ◽  
Tony Muchamuel ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Lavage Fluid ◽  
Lung Infection ◽  
Gamma Interferon ◽  
Pcr Analysis ◽  
Interleukin 18 ◽  
Legionnaires Disease ◽  
Ifn Γ

ABSTRACT The in vivo role of endogenous interleukin-18 (IL-18) in modulating gamma interferon (IFN-γ)-mediated resolution of replicativeLegionella pneumophila lung infection was assessed using a murine model of Legionnaires' disease. Intratracheal inoculation of A/J mice with virulent bacteria (106 L. pneumophila organisms per mouse) resulted in induction of IL-18 protein in bronchoalveolar lavage fluid (BALF) and intrapulmonary expression of IL-18 mRNA. Real-time quantitative RT-PCR analysis of infected lung tissue demonstrated that induction of IL-18 in BALF preceded induction of IL-12 and IFN-γ mRNAs in the lung. Blocking intrapulmonary IL-18 activity by administration of a monoclonal antibody (MAb) to the IL-18 receptor (anti-IL-18R MAb) prior toL. pneumophila infection inhibited induction of intrapulmonary IFN-γ production but did not significantly alter resolution of replicative L. pneumophila lung infection. In contrast, blocking endogenous IL-12 activity by administration of anti-IL-12 MAb) alone or in combination with anti-IL-18R MAb inhibited induction of intrapulmonary IFN-γ and resulted in enhanced intrapulmonary growth of the bacteria within 5 days postinfection. Taken together, these results demonstrate that IL-18 plays a key role in modulating induction of IFN-γ in the lung in response to L. pneumophila and that together with IL-12, IL-18 regulates intrapulmonary growth of the bacteria.

Studies on cytokine activation of listericidal activity in murine macrophages

1990 ◽  
Vol 36 (10) ◽  
pp. 671-675 ◽  
Author(s):  
Michel Denis ◽  
Evan O. Gregg
Keyword(s):  
Peritoneal Macrophages ◽  
Interferon Γ ◽  
Necrosis Factor Alpha ◽  
Cytokine Activation ◽  
Inhibition Of Growth ◽  
Cytokine Treatment ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ

The ability of a variety of soluble factors, alone or in combination, to endow murine resident peritoneal macrophages with listericidal activity was assessed. Inhibition of growth and (or) killing of Listeria in infected macrophages was determined by the uptake of [3H]uracil following lysis of the infected macrophage monolayers. Interferon-γ was shown to induce modest listericidal activity in murine resident macrophages as compared with untreated monolayers. Treatment with tumour necrosis factor alpha also induced significant listericidal activity in this system. Among other cytokines tested, IL-4 induced an ability to inhibit growth of Listeria in resident macrophages. The ability of cytokines to act in an additive or synergistic fashion with IFN-γ was also investigated. Combinations of IFN-γ and IL-4 and IFN-γ and IL-2 induced listericidal activity not greater than that seen with IFN-γ alone. IFN-γ and TNF-α were shown to increase bactericidal activity in an additive fashion. However, elicited macrophages were shown to spontaneously exert a significant listericidal activity that was not enhanced by cytokine treatment. Collectively, these findings show that cytokine treatment induced rather modest enhancement in listericidal activity in murine resident peritoneal macrophages and no enhancement whatsoever in elicited macrophages. Thus, in in vivo situations where Listeria organisms are completely cleared from the infected organs, mechanisms other than lymphokine-induced listericidal activity of resident macrophages would seem to be operating. Key words: Listeria, macrophages, cytokines.

scholarly journals Modulation of Cytokine Response of Pneumonic Foals by Virulent Rhodococcus equi

1999 ◽  
Vol 67 (10) ◽  
pp. 5041-5047 ◽  
Author(s):  
Steeve Giguère ◽  
Bruce N. Wilkie ◽  
John F. Prescott
Keyword(s):  
T Lymphocytes ◽  
Mrna Expression ◽  
Rhodococcus Equi ◽  
Cytokine Response ◽  
Interleukin 12 ◽  
Virulence Plasmid ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ

ABSTRACT The ability of Rhodococcus equi to induce pneumonia in foals depends on the presence of an 85- to 90-kb plasmid. In this study, we evaluated whether plasmid-encoded products mediate virulence by modulating the cytokine response of foals. Foals infected intrabronchially with a virulence plasmid-containing strain of R. equi had similar gamma interferon (IFN-γ) and interleukin-12 (IL-12) p35 but significantly higher IL-1β, IL-10, IL-12 p40, and tumor necrosis factor alpha (TNF-α) mRNA expression in lung tissue compared to foals infected with the plasmid-cured derivative. IFN-γ mRNA expression levels in CD4+ T lymphocytes isolated from bronchial lymph nodes (BLN) were similar for the two groups of R. equi-infected foals on day 3 postinfection. However, on day 14, in association with pneumonia and marked multiplication of virulentR. equi but with complete clearance of the plasmid-cured derivative, IFN-γ mRNA expression in BLN CD4+ T lymphocytes was significantly (P < 0.001) higher in foals infected with the plasmid-cured derivative. These results suggests an immunomodulating role for R. equi virulence plasmid-encoded products in downregulating IFN-γ mRNA expression by CD4+ T lymphocytes.

scholarly journals Nramp1 Is Not a Major Determinant in the Control of Brucella melitensis Infection in Mice

2003 ◽  
Vol 71 (2) ◽  
pp. 621-628 ◽  
Author(s):  
Laurence A. Guilloteau ◽  
Jacques Dornand ◽  
Antoine Gross ◽  
Michel Olivier ◽  
Fabienne Cortade ◽  
...  
Keyword(s):  
Brucella Melitensis ◽  
Natural Resistance ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Reverse Transcription Pcr ◽  
Tnf Α ◽  
Ifn Γ ◽  
Oxide Synthase

ABSTRACT Brucella, the causative agent of brucellosis in animals and humans, can survive and proliferate within macrophages. Macrophages mediate mouse resistance to various pathogens through the expression of the Nramp1 gene. The role of this gene in the control of Brucella infection was investigated. When BALB/c mice (Nramp1s ) and C.CB congenic mice (Nramp1r ) were infected with Brucella melitensis, the number of Brucella organisms per spleen was significantly larger in the C.CB mice than in the BALB/c mice during the first week postinfection (p.i.). This Nramp1-linked susceptibility to Brucella was temporary, since similar numbers of Brucella were recovered from the two strains of mice 2 weeks p.i. The effect of Nramp1 expression occurred within splenocytes intracellularly infected by Brucella. However, there was no difference between in vitro replication rates of Brucella in macrophages isolated from the two strains of mice infected in vivo or in Nramp1 RAW264 transfectants. In mice, infection with Brucella induced an inflammatory response, resulting in splenomegaly and recruitment of phagocytes in the spleen, which was amplified in C.CB mice. Reverse transcription-PCR (RT-PCR), performed 5 days p.i., showed that inducible nitric oxide synthase, tumor necrosis factor alpha (TNF-α), interleukin-12 p40 (IL-12p40), gamma interferon (IFN-γ), and IL-10 mRNAs were similarly induced in spleens of the two strains. In contrast, the mRNA of KC, a C-X-C chemokine, was induced only in infected C.CB mice at this time. This pattern of mRNA expression was maintained at 14 days p.i., with IFN-γ and IL-12p40 mRNAs being more intensively induced in the infected C.CB mice, but TNF-α mRNA was no longer induced. The higher recruitment of neutrophils observed in the spleens of infected C.CB mice could explain the temporary susceptibility of C.CB mice to B. melitensis infection. In contrast to infections with Salmonella, Leishmania, and Mycobacterium, the expression of the Nramp1 gene appears to be of limited importance for the natural resistance of mice to Brucella.

scholarly journals Critical Role for Tumor Necrosis Factor Alpha in Controlling the Number of Lumenal Pathogenic Bacteria and Immunopathology in Infectious Colitis

2001 ◽  
Vol 69 (11) ◽  
pp. 6651-6659 ◽  
Author(s):  
Nathalie S. Gonçalves ◽  
Marjan Ghaem-Maghami ◽  
Giovanni Monteleone ◽  
Gad Frankel ◽  
Gordon Dougan ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Infectious Colitis ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Infection of mice with the intestinal bacterial pathogenCitrobacter rodentium results in colonic mucosal hyperplasia and a local Th1 inflammatory response similar to that seen in mouse models of inflammatory bowel disease. In these latter models, and in patients with Crohn's disease, neutralization of tumor necrosis factor alpha (TNF-α) is of therapeutic benefit. Since there is no information on the role of TNF-α in either immunity to noninvasive bacterial pathogens or on the role of TNF-α in the immunopathology of infectious colitis, we investigated C. rodentiuminfection in TNFRp55−/− mice. In TNFRp55−/−mice, there were higher colonic bacterial burdens, but the organisms were cleared at the same rate as C57BL/6 mice, showing that TNF-α is not needed for protective antibacterial immunity. The most striking feature of infection in TNFRp55−/−mice, however, was the markedly enhanced pathology, with increased mucosal weight and thickness, increased T-cell infiltrate, and a markedly greater mucosal Th1 response. Interleukin-12 p40 transcripts were markedly elevated in C. rodentium-infected TNFRp55−/− mice, and this was associated with enhanced mucosal STAT4 phosphorylation. TNF-α is not obligatory for protective immunity to C. rodentium in mice; however, it appears to play some role in downregulating mucosal pathology and Th1 immune responses.

scholarly journals CD40 Ligation Prevents Trypanosoma cruziInfection through Interleukin-12 Upregulation

1999 ◽  
Vol 67 (4) ◽  
pp. 1929-1934 ◽  
Author(s):  
Damien Chaussabel ◽  
Frédérique Jacobs ◽  
Jan de Jonge ◽  
Marijke de Veerman ◽  
Yves Carlier ◽  
...  
Keyword(s):  
De Novo ◽  
Critical Role ◽  
Interleukin 12 ◽  
No Production ◽  
Cd40 Ligation ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT Because of the critical role of the CD40-CD40 ligand (CD40L) pathway in the induction and effector phases of immune responses, we investigated the effects of CD40 ligation on the control ofTrypanosoma cruzi infection. First, we observed that supernatants of murine spleen cells stimulated by CD40L-transfected 3T3 fibroblasts (3T3-CD40L transfectants) prevent the infection of mouse peritoneal macrophages (MPM) by T. cruzi. This phenomenon depends on de novo production of nitric oxide (NO) as it is prevented by the addition of N-nitro-l-arginine methyl ester, a NO synthase inhibitor. NO production requires interleukin (IL)-12-mediated gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) synthesis as demonstrated by inhibition experiments using neutralizing anti-IL-12, anti-IFN-γ, and anti-TNF-α monoclonal antibodies (MAb). We found that an activating anti-CD40 MAb also directly stimulates IFN-γ-activated MPM to produce NO and thereby to control T. cruzi infection. To determine the in vivo relevance of these in vitro findings, mice were injected with 3T3-CD40L transfectants or 3T3 control fibroblasts at the time ofT. cruzi inoculation. We observed that in vivo CD40 ligation dramatically reduced both parasitemia and the mortality rate of T. cruzi-infected mice. A reduced parasitemia was still observed when the injection of 3T3-CD40L transfectants was delayed 8 days postinfection. It was abolished by injection of anti-IL-12 MAb. Taken together, these data establish that CD40 ligation facilitates the control of T. cruzi infection through a cascade involving IL-12, IFN-γ, and NO.

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