Lps<sup>d</sup>/Ran of endotoxin-resistant C3H/HeJ mice is defective in mediating lipopolysaccharide endotoxin responses

Wong, Pierre; Kang, Anthony D.; Chen, Hong; Yuan, Quan; Fan, Peidong; Sultzer, Barnet M.; Kan, Yuet Wai; Chung, Siu-Wah

doi:10.1073/pnas.96.20.11543

Cited by 45 publications

(63 citation statements)

References 51 publications

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“…Many of these molecules have been implicated in the development of endotoxin tolerance. In addition, negative regulators of NF-κB activation, such as Ran GTPase, A20 binding inhibitor of NF-κB activation-1 and -2 (ABIN-1 and -2), and dual specificity phosphatase 1 (DUSP1), have been shown to limit inflammatory gene expression, including during experimental endotoxininduced shock (53)(54)(55)(56)(57). It is expected that multiple inhibitory pathways are activated during the course of sepsis that function to limit the magnitude of macrophage-driven inflammation.…”

Section: Figurementioning

confidence: 99%

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

Deng

Cheng

Newstead

et al. 2006

Journal of Clinical Investigation

166

252

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Sepsis results in a state of relative immunosuppression, rendering critically ill patients susceptible to secondary infections and increased mortality. Monocytes isolated from septic patients and experimental animals display a "deactivated" phenotype, characterized by impaired inflammatory and antimicrobial responses, including hyporesponsiveness to LPS. We investigated the role of the LPS/TLR4 axis and its inhibitor, IL-1 receptor-associated kinase-M (IRAK-M), in modulating the immunosuppression of sepsis using a murine model of peritonitis-induced sepsis followed by secondary challenge by intratracheal Pseudomonas aeruginosa. Septic mice demonstrated impaired alveolar macrophage function and increased mortality when challenged with intratracheal Pseudomonas as compared with nonseptic controls. TLR2 and TLR4 expression was unchanged in the lung following sepsis, whereas levels of IRAK-M were upregulated. Macrophages from IRAK-M-deficient septic mice produced higher levels of proinflammatory cytokines ex vivo and greater costimulatory molecule expression in vivo as compared with those of their WT counterparts. Following sepsis and secondary intrapulmonary bacterial challenge, IRAK-M -/-animals had higher survival rates and improved bacterial clearance from lung and blood compared with WT mice. In addition, increased pulmonary chemokine and inflammatory cytokine production was observed in IRAK-M -/-animals, leading to enhanced neutrophil recruitment to airspaces. Collectively, these findings indicate that IRAK-M mediates critical aspects of innate immunity that result in an immunocompromised state during sepsis.

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Section: Figurementioning

confidence: 99%

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

Deng

Cheng

Newstead

et al. 2006

Journal of Clinical Investigation

166

252

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“…C3H/HeJ mice have a missense mutation in the third exon of TLR-4, yielding a nonfunctional TLR-4, and are hyporesponsive to the effects of LPS [24][25][26] and are resistant to lethal endotoxin-induced shock as compared with normal mice. 27 The simultaneous induction of the principal acute-phasecytokines suggests that a local paracrine mechanism may be responsible for these changes in the expression of genes involved in the regulation of hepatic iron metabolism.…”

mentioning

confidence: 99%

Phagocytosis of gadolinium chloride or zymosan induces simultaneous upregulation of hepcidin- and downregulation of hemojuvelin- and Fpn-1-gene expression in murine liver

Moriconi

Ahmad

Ramadori

et al. 2009

Laboratory Investigation

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The liver and the spleen are the organs in which cellular material and aged erythrocytes are eliminated from the blood. Within the liver, Kupffer cells (KCs) are mainly responsible for this task, as such KCs have a pivotal role in iron metabolism. The aim of this study is to investigate the changes of hepatic gene expression in two models of KC phagocytosis. Gadolinium chloride (GD) or zymosan was injected intraperitoneally into rats and to endotoxin-resistant mice (C3H/HeJ). The animals were killed at different time points and their livers were immediately frozen in liquid nitrogen for RNA isolation and immunohistological studies. RNA was analyzed by real-time PCR and northern blot. Sera were used to measure transaminases, hepcidin and iron levels. The expression of iron metabolism genes, hepcidin, hemojuvelin (Hjv), ferroportin-1 (Fpn-1) and of the inflammatory cytokines IL-6, IL-1b, TNF-a and IFN-g was determined. Although phagocytosed material was detected in ED-1-and C1q-positive cells, no inflammatory cells were identified within the liver parenchyma. Serum levels of hepcidin, iron and transaminases did not differ from those of control animals. Both GD and zymosan induced an upregulation of hepcidin-gene expression in rat liver as early as 3 h, reaching a maximum 6 h after treatment. Hjv-and Fpn-1-gene expression was downregulated at the same time. IL-6 was by far the most induced acute-phase-cytokine in GD-and zymosan-treated livers, although IL-1b and TNF-a were also strongly upregulated by zymosan and to a lesser extent by GD. Similar results were obtained in the C3H/HeJ mouse strain excluding the possible role of contaminating endotoxin. This study shows that phagocytosis upregulates hepcidin-gene expression and downregulates Hjv-and Fpn-1-gene expression within the liver. These changes in iron-regulating-gene expression may be mediated by the locally produced acute-phase-cytokines.

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“…Adenoviral transfer and ex-pression of RanC/d allele leads to down-modulation of proinflammatory cytokine production in vitro and in vivo and protection against septic shock in mice (17)(18)(19)(20). In this report, we present data to demonstrate a difference in tissue distribution between RanC/d-and RanT/n-transduced cells in 2 h or less after infection.…”

mentioning

confidence: 52%

“…All adenovirus stocks were prepared from human embryonic kidney 293 cells as described previously (17,18). The stocks were purified by CsCl banding twice, dialyzed, aliquoted, and stored at Ϫ80°C until use.…”

Section: Methodsmentioning

confidence: 99%

“…Inoculation-We showed previously that expression of RanC/d in macrophages in vitro resulted in reduced production of tumor necrosis factor-␣ and that intraperitoneal inoculation of our Ad vector carrying RanC/d protected mice from septic shock (17,20,23). Because the peritoneal cavity contains mainly resident macrophages, we sought to determine whether intraperitoneal administration would lead to effective down-modulation of host innate immune response.…”

Section: Tissue Distribution Of Viral Dna Affected By the Route Ofmentioning

confidence: 99%

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Presence of Prepackaged mRNA in Virions of DNA Adenovirus

Chung

Arnott

Yang

et al. 2003

Journal of Biological Chemistry

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Ran GTPase has been shown to be involved in host innate immune response, and two alleles, RanT/n and RanC/d, which differ from each other by a single nucleotide, have opposite effects on host innate immune response. In this study, we showed that although intravenous administration in mice with either Ran cDNA using an identical adenovirus (Ad) vector resulted in no significant difference in vector tissue distribution, intraperitoneal administration resulted in effective vector transduction into peritoneal macrophages, coupled with a striking difference in vector tissue distribution in 2 h or less. We further demonstrated the presence of prepackaged RNA in virions of Ad vectors, in cells actively producing Ad virus particles, and in cells very shortly after Ad infection. Real-time PCR analysis confirmed the presence of prepackaged RNA and estimated the copy number to be one per viral genome. The prepackaged viral mRNA could be used for translation into proteins, as shown by experiments in which the transcriptional inhibitor actinomycin-D was used. Hence, translation of Ran proteins from prepackaged viral mRNA immediately after virus uncoating in the cytoplasm is one mechanism that would account for an early difference in Ad-vector tissue distribution after efficient gene transfer into macrophages.

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Lps^d/Ran of endotoxin-resistant C3H/HeJ mice is defective in mediating lipopolysaccharide endotoxin responses

Cited by 45 publications

References 51 publications

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

Phagocytosis of gadolinium chloride or zymosan induces simultaneous upregulation of hepcidin- and downregulation of hemojuvelin- and Fpn-1-gene expression in murine liver

Presence of Prepackaged mRNA in Virions of DNA Adenovirus

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Lpsd/Ran of endotoxin-resistant C3H/HeJ mice is defective in mediating lipopolysaccharide endotoxin responses

Cited by 45 publications

References 51 publications

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

Phagocytosis of gadolinium chloride or zymosan induces simultaneous upregulation of hepcidin- and downregulation of hemojuvelin- and Fpn-1-gene expression in murine liver

Presence of Prepackaged mRNA in Virions of DNA Adenovirus

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Lps^d/Ran of endotoxin-resistant C3H/HeJ mice is defective in mediating lipopolysaccharide endotoxin responses