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  • The American Association of Immunologists  (6)
  • 1
    Online Resource
    Online Resource
    Hemozoin Increases IFN-γ-Inducible Macrophage Nitric Oxide Generation Through Extracellular Signal-Regulated Kinase- and NF-κB-Dependent Pathways
    The American Association of Immunologists ; 2003
    In:  The Journal of Immunology Vol. 171, No. 8 ( 2003-10-15), p. 4243-4253
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 171, No. 8 ( 2003-10-15), p. 4243-4253
    Abstract: NO overproduction has been suggested to contribute to the immunopathology related to malaria infection. Even though a role for some parasite molecules (e.g., GPI) in NO induction has been proposed, the direct contribution of hemozoin (HZ), another parasite metabolite, remains to be established. Therefore, we were interested to determine whether Plasmodium falciparum (Pf) HZ and synthetic HZ, β-hematin, alone or in combination with IFN-γ, were able to induce macrophage (Mφ) NO synthesis. We observed that neither Pf HZ nor synthetic HZ led to NO generation in B10R murine Mφ; however, they significantly increased IFN-γ-mediated inducible NO synthase (iNOS) mRNA and protein expression, and NO production. Next, by investigating the transductional mechanisms involved in this cellular regulation, we established that HZ induces extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase phosphorylation as well as NF-κB binding to the iNOS promoter, and enhances the IFN-γ-dependent activation of both second messengers. Of interest, cell pretreatment with specific inhibitors against either NF-κB or the ERK1/2 pathway blocked the HZ + IFN-γ-inducible NF-κB activity and significantly reduced the HZ-dependent increase on IFN-γ-mediated iNOS and NO induction. Even though selective inhibition of the Janus kinase 2/STAT1α pathway suppressed NO synthesis in response to HZ + IFN-γ, HZ alone did not activate this signaling pathway and did not have an up-regulating effect on the IFN-γ-induced Janus kinase 2/STAT1α phosphorylation and STAT1α binding to the iNOS promoter. In conclusion, our results suggest that HZ exerts a potent synergistic effect on the IFN-γ-inducible NO generation in Mφ via ERK- and NF-κB-dependent pathways.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.171.8.4243
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2003
    detail.hit.zdb_id: 1475085-5
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  • 2
    Online Resource
    Online Resource
    Cutting Edge: STAT1 and T-bet Play Distinct Roles in Determining Outcome of Visceral Leishmaniasis Caused by Leishmania donovani
    The American Association of Immunologists ; 2006
    In:  The Journal of Immunology Vol. 177, No. 1 ( 2006-07-01), p. 22-25
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 177, No. 1 ( 2006-07-01), p. 22-25
    Abstract: T-bet and STAT1 regulate IFN-γ gene transcription in CD4+ T cells, which mediate protection against Leishmania. Here we show that T-bet and STAT1 are required for the induction of an efficient Th1 response during Leishmania donovani infection, but they play distinct roles in determining disease outcome. Both STAT1−/− and T-bet−/− mice failed to mount a Th1 response, but STAT1−/− mice were highly resistant to L. donovani and developed less immunopathology, whereas T-bet−/− mice were highly susceptible and eventually developed liver inflammation. Adoptive cell transfer studies showed that RAG2−/− recipients receiving STAT1+/+ or STAT1−/− T cells developed comparable liver pathology, but those receiving STAT1−/− T cells were significantly more susceptible to infection. These unexpected findings reveal distinct roles for T-bet and STAT1 in mediating host immunity and liver pathology during visceral leishmaniasis.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.177.1.22
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2006
    detail.hit.zdb_id: 1475085-5
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  • 3
    Online Resource
    Online Resource
    Protein Tyrosine Phosphatases Regulate Asthma Development in a Murine Asthma Model
    The American Association of Immunologists ; 2009
    In:  The Journal of Immunology Vol. 182, No. 3 ( 2009-02-01), p. 1334-1340
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 182, No. 3 ( 2009-02-01), p. 1334-1340
    Abstract: Allergic asthma is a chronic inflammatory disease characterized by Th2-type inflammation. Although the cellular interactions are now well studied, the intracellular signaling involved in asthma development is still a developing field. Protein tyrosine kinases are one focus of such research and their inhibition shows improvement of asthmatic features. Interestingly, very little attention was given to protein tyrosine phosphatases (PTPs), the counterparts to protein tyrosine kinases, in the development of asthma. Previous studies from our laboratory showed that pharmacological inhibition of PTPs induced a transient Th1 response in the spleen. Therefore, we hypothesized that modulation of PTPs could influence asthma development. To assess PTP functions, we used the PTP inhibitor bis-peroxovanadium bpV(phen) in a murine model of asthma during either allergen sensitization or challenge. Inhibition of PTPs during allergen sensitization resulted in the reduction of key features of allergic asthma: serum IgE levels, lung tissue inflammation, eosinophilia, and airway hyperresponsiveness. Of utmost interest, PTP inhibition at allergen challenge resulted in a very similar improvement of asthmatic features. Of further importance, we observed that bpV(phen) treatment modulated cytokine expression in the spleen and, more specifically, favored Th1 cytokines while inhibiting Th2 cytokines. Collectively, we show for the first time that intact activity of PTPs is required for a complete induction of asthma in a mouse model. This clearly suggests that PTPs have a pivotal regulatory role in the development of asthmatic diseases, which opens the possibility of new therapeutic avenues.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.182.3.1334
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2009
    detail.hit.zdb_id: 1475085-5
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  • 4
    Online Resource
    Online Resource
    Secretory Leukocyte Protease Inhibitor Plays an Important Role in the Regulation of Allergic Asthma in Mice
    The American Association of Immunologists ; 2011
    In:  The Journal of Immunology Vol. 186, No. 7 ( 2011-04-01), p. 4433-4442
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 186, No. 7 ( 2011-04-01), p. 4433-4442
    Abstract: Secretory leukocyte protease inhibitor (SLPI) is an anti-inflammatory protein that is observed at high levels in asthma patients. Resiquimod, a TLR7/8 ligand, is protective against acute and chronic asthma, and it increases SLPI expression of macrophages in vitro. However, the protective role played by SLPI and the interactions between the SLPI and resiquimod pathways in the immune response occurring in allergic asthma have not been fully elucidated. To evaluate the role of SLPI in the development of asthma phenotypes and the effect of resiquimod treatment on SLPI, we assessed airway resistance and inflammatory parameters in the lungs of OVA-induced asthmatic SLPI transgenic and knockout mice and in mice treated with resiquimod. Compared with wild-type mice, allergic SLPI transgenic mice showed a decrease in lung resistance (p & lt; 0.001), airway eosinophilia (p & lt; 0.001), goblet cell hyperplasia (p & lt; 0.001), and plasma IgE levels (p & lt; 0.001). Allergic SLPI knockout mice displayed phenotype changes significantly more severe compared with wild-type mice. These phenotypes included lung resistance (p & lt; 0.001), airway eosinophilia (p & lt; 0.001), goblet cell hyperplasia (p & lt; 0.001), cytokine levels in the lungs (p & lt; 0.05), and plasma IgE levels (p & lt; 0.001). Treatment of asthmatic transgenic mice with resiquimod increased the expression of SLPI and decreased inflammation in the lungs; resiquimod treatment was still effective in asthmatic SLPI knockout mice. Taken together, our study showed that the expression of SLPI protects against allergic asthma phenotypes, and treatment by resiquimod is independent of SLPI expression, displayed through the use of transgenic and knockout SLPI mice.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1001539
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2011
    detail.hit.zdb_id: 1475085-5
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  • 5
    Online Resource
    Online Resource
    Attenuation of MHC Class II Expression in Macrophages Infected with Mycobacterium bovis Bacillus Calmette-Guerin Involves Class II Transactivator and Depends on the Nramp1 Gene
    The American Association of Immunologists ; 1999
    In:  The Journal of Immunology Vol. 163, No. 5 ( 1999-09-01), p. 2688-2696
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 163, No. 5 ( 1999-09-01), p. 2688-2696
    Abstract: The natural resistance associated macrophage protein 1 (Nramp1) gene determines the ability of murine macrophages to control infection with a group of intracellular pathogens, including Salmonella typhimurium, Leishmania donovani, and Mycobacterium bovis bacillus Calmette-Guérin (BCG). The expression of the resistant allele of the Nramp1 gene in murine macrophages is associated with a more efficient expression of several macrophage activation-associated genes, including class II MHC loci. In this study, we investigated the molecular mechanisms involved in IFN-γ-induced MHC class II expression in three types of macrophages: those expressing a wild-type allele of the Nramp1 gene (B10R and 129/Mφ), those carrying a susceptible form of the Nramp1 gene (B10S), and those derived from 129-Nramp1-knockout mice (129/Nramp1-KO). Previously, we published results showing that Ia protein expression is significantly higher in the IFN-γ-induced B10R macrophages, compared with its susceptible counterpart. In this paper, we also show that the higher expression of Ia protein in B10R cells is associated with higher I-Aβ mRNA expression, which correlates with a higher level of IFN-γ-induced phosphorylation of the STAT1-α protein and subsequently with elevated expression of class II transactivator (CIITA) mRNA, compared with B10S. Furthermore, we demonstrate that the infection of macrophages with M. bovis BCG results in a down-regulation of CIITA mRNA expression and, consequently, in the inhibition of Ia induction. Therefore, our data explain, at least in part, the molecular mechanism involved in the inhibition of I-Aβ gene expression in M. bovis BCG-infected macrophages activated with IFN-γ.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.163.5.2688
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 1999
    detail.hit.zdb_id: 1475085-5
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  • 6
    Online Resource
    Online Resource
    Abrupt Expression of TLR4 in TLR4-Deficient Macrophages Imposes a Selective Disadvantage: Genetic Evidence for TLR4-Dependent Responses to Endogenous, Nonmicrobial Stimuli
    The American Association of Immunologists ; 2006
    In:  The Journal of Immunology Vol. 176, No. 2 ( 2006-01-15), p. 1185-1194
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 176, No. 2 ( 2006-01-15), p. 1185-1194
    Abstract: TLR4 is crucial for macrophage responses to LPS. It is less clear whether TLR4 may also transduce signals from host factors, and if so, with what consequences. Immortalized bone marrow-derived macrophage cell lines, termed T4Cr and T4ko, were established from TLR4null strains, C57BL/10ScNCr and TLR4 knockout mice, respectively. Multiple transfections and selections were conducted to stably introduce TLR4 into these cell lines. Among 196 individual clones isolated, 48 expressed TLR4 on the cell surface but did not respond to LPS due to a deletion in the MyD88 gene. The remaining clones integrated TLR4 DNA into the genome but expressed neither detectable TLR4 mRNA nor TLR4 protein. To test the possibility that TLR4null cells lack modulating factors to protect against a harmful effect of TLR4, 15 stably transfected clones were generated in the presence of conditioned media from wild-type macrophages. Some of these cells expressed a small amount of TLR4 and regained responsiveness to LPS. Because no microbial ligands were available to the cell lines during their generation, signaling via endogenous ligands is likely to have occurred in TLR4-expressing, signal-competent macrophages and imposed a proliferative or other selective disadvantage. These studies support the existence of constitutive signaling via TLR4 during in vitro culture of macrophages without microbial products, and help account for the lack of reports of restoration of TLR4 expression in normally TLR4-expressing types of cells in vitro whose TLR4 genes are deleted or disrupted.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.176.2.1185
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2006
    detail.hit.zdb_id: 1475085-5
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