Role of Interferon-  in Experimental Gram-Negative Sepsis

Silva, Ayona T.; Cohen, Jonathan

doi:10.1093/infdis/166.2.331

Cited by 89 publications

(46 citation statements)

References 17 publications

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“…As periodical comprehensive serology and histopathology revealed no indication of pathogens, the bacteria may have been enteric. This is consistent with the data indicating that IFN-y plays a significant role in the pathogenesis of Gram-negative sepsis (23).…”

Section: Discussionsupporting

confidence: 93%

Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver.

Toyonaga

Hino

Sugai

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

204

116

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Interferon-y may play an important role in the immune response and in inflammatory diseases, including chronic active hepatitis. To understand the role of interferon-y in the regulation of inflammation and to establish a mouse model of chronic active hepatitis, we produced transgenic mice in which the mouse interferon-y gene was regulated by a liver-specific promoter, the serum amyloid P component gene promoter. Four transgenic mouse lines were generated, and two of these lines expressed mRNA of interferon-y in the liver. Levels of serum transaminases increased gradually as a function of age and were significantly higher than those of interferon--negative littermates after 4 weeks after birth. One transgenic mouse line showed a histology of chronic active hepatitis similar to that found in human patients, although cirrhotic changes such as fibrosis were scarce. Thus, the liver-specific production of interferon-y is sufficient to induce chronic inflammatory disease and this mouse is a transgenic model of chronic active hepatitis.Chronic hepatic diseases, such as chronic active hepatitis and liver cirrhosis, are public health problems of worldwide importance and are major causes of mortality in certain areas of the world. Clinical and epidemiological studies (1-4) have clearly shown the importance of hepatitis B and C viruses (HBV, HCV) in chronic active hepatitis as well as hepatocellular carcinoma (HCC). Furthermore, studies ofpathology revealed that HCC arises in a cirrhotic liver and that chronic hepatitis is prerequisite for the development of HCC. The mechanisms responsible for HBV-or HCV-induced hepatocellular injury are not well understood. However, it is generally accepted that HBV is not directly cytopathic and that liver cell necrosis is dependent upon the host's immune response, directed at viral determinants on the hepatocyte membrane (5, 6). This immune response is mainly mediated by cytotoxic T lymphocytes (7).Several transgenic models of hepatic disease have been described. Chisari et al. (8) (10) showed that transgenic mice expressing the albumin-plasminogen activator gene develop progressive degenerative change in the liver due to accumulation ofRER-bounded multivesicular bodies. However, the principal lesion in these models appears to involve the hepatocyte secretory pathway and thus is different from that found in human patients.A model of acute hepatitis can be produced by administration of chemicals. However, remaining hepatocytes are induced to proliferate until the liver regains its original weight. Shull et al. (11) produced transforming growth factor (TGF)-,81-deficient mice. These mice developed an inflammatory liver disease similar to that found in HBV infection. However, about 20 days after birth these mice died due to a wasting syndrome. Mori et al. (12) demonstrated that liver changes histologically mimicking human hepatitis were produced in the mouse liver after repeated immunization with syngeneic crude liver proteins. However, it is not known whether hepatitis continues l...

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Section: Discussionsupporting

confidence: 93%

Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver.

Toyonaga

Hino

Sugai

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

204

116

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“…These results suggest a protective role for IFN-ã in host responses to these pathogens. In contrast, it was reported that administration of a monoclonal antibody to IFN-ã before or after Escherichia coli challenge in an experimental gramnegative sepsis model protected mice from death [15]. In the present study, BALF IFN-ã levels in strain DT-X-infected mice were higher than those in strain DT-Sinfected mice at all time points.…”

Section: Discussioncontrasting

confidence: 85%

Induction of interleukin-10 and down-regulation of cytokine production by Klebsiella pneumoniae capsule in mice with pulmonary infection

Yoshida¹,

Matsumoto

Tateda

et al. 2001

Journal of Medical Microbiology

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The role of the capsule of Klebsiella pneumoniae in inducing cytokine production was investigated by comparing the responses of mice with experimentally induced pneumonia caused by capsulate (strain DT-S) or non-capsulate (mutant strain DT-X) K. pneumoniae. Anaesthetised ICR mice were inoculated intranasally. Whereas all DT-S-infected mice died within 3 days, no deaths were observed in DT-X-infected mice by 14 days after infection. During the early stage of infection, interferon-ã (IFN-ã) levels in bronchoalveolar lavage¯uid (BALF) of DT-X-infected mice were signi®cantly higher than those in DT-S-infected mice. In contrast, in the late stage of infection, serum levels of granulocyte macrophage-colony stimulating factor (GM-CSF) and IFN-ã in DT-Sinfected mice were signi®cantly higher than those in DT-X-infected mice. Levels of interleukin-10 (IL-10) in BALF and serum of DT-S-infected mice were signi®cantly and persistently higher than those of DT-X-infected mice. The IL-10=TNF-á (tumour necrosis factor-á) ratios in BALF and serum indicated that higher levels of IL-10 production were induced in mice infected with strain DT-S than in those infected with strain DT-X. The results suggest that the capsule of K. pneumoniae may induce IL-10 production at the site of infection and, thereafter, these high IL-10 levels may serve to down-regulate the expression of pro-in¯ammatory cytokines.

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“…We show in this study that defective type I IFN signaling results in impaired host resistance to different extracellular pathogens, including GBS, S. pneumoniae, and E. coli. The effect of IFN-␣␤R deficiency was marked, with mortality surpassing that seen in the absence of IFN-␥ signaling, a function considered crucial for host defenses against intracellular (3), as well as extracellular (41,42,44) bacteria. Interestingly, IFN-␣␤R Ϫ/Ϫ and IFN-␥R Ϫ/Ϫ double KO mice showed an extremely severe, additive phenotype and quickly succumbed to challenge with few CFU of GBS.…”

Section: Discussionmentioning

confidence: 99%

“…IFN-␥R Ϫ/Ϫ and double KO IFN-␣␤ and IFN-␥R Ϫ/Ϫ mice were also studied for comparison, because IFN-␥ is known to play a central role in defenses against intracellular (3,40) as well as extracellular (41,42) bacteria, including GBS (43)(44)(45). Fig.…”

Section: Ifn-␣␤r-deficient Neonatal Mice Are Hypersusceptible To Gbs mentioning

confidence: 99%

Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria

Mancuso

Midiri

Biondo

et al. 2007

The Journal of Immunology

222

214

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It is known that host cells can produce type I IFNs (IFN-αβ) after exposure to conserved bacterial products, but the functional consequences of such responses on the outcome of bacterial infections are incompletely understood. We show in this study that IFN-αβ signaling is crucial for host defenses against different bacteria, including group B streptococci (GBS), pneumococci, and Escherichia coli. In response to GBS challenge, most mice lacking either the IFN-αβR or IFN-β died from unrestrained bacteremia, whereas all wild-type controls survived. The effect of IFN-αβR deficiency was marked, with mortality surpassing that seen in IFN-γR-deficient mice. Animals lacking both IFN-αβR and IFN-γR displayed additive lethality, suggesting that the two IFN types have complementary and nonredundant roles in host defenses. Increased production of IFN-αβ was detected in macrophages after exposure to GBS. Moreover, in the absence of IFN-αβ signaling, a marked reduction in macrophage production of IFN-γ, NO, and TNF-α was observed after stimulation with live bacteria or with purified LPS. Collectively, our data document a novel, fundamental function of IFN-αβ in boosting macrophage responses and host resistance against bacterial pathogens. These data may be useful to devise alternative strategies to treat bacterial infections.

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Role of Interferon- in Experimental Gram-Negative Sepsis

Cited by 89 publications

References 17 publications

Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver.

Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver.

Induction of interleukin-10 and down-regulation of cytokine production by Klebsiella pneumoniae capsule in mice with pulmonary infection

Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria

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