Down-regulation of Bgp1a Viral Receptor by Interferon-γ Is Related to the Antiviral State and Resistance to Mouse Hepatitis Virus 3 Infection

Vassão, Ruth Camargo; Franco, Milene Tino De; Hartz, Dieter; Modolell, Manuel; Sippel, Albrecht E.; Pereira, Carlos Augusto

doi:10.1006/viro.2000.0463

Cited by 12 publications

(27 citation statements)

References 33 publications

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“…By using gene expression profiling to evaluate the mRNA content of IFN-γ-activated macrophages we attempted to provide detailed information about up-or down-regulated gene products to be in turn linked to the modulation of biological macrophage functions. As an example using a classical approach, we previously identified the regulation of the main MHV3 receptor gene expression in IFN-γ-activated macrophages as a central feature of resistance (7). The gene expression profiling shown here confirmed these previous data.…”

Section: Introductionsupporting

confidence: 86%

“…Studies on the expression of genes coding for virus receptors and on virus binding to membrane proteins from IFN-γ-activated macrophages showed down-regulation of virus receptor expression only in macrophages from the resistant A/J mice (7). Thus, the in vitro ability of activated A/J macrophages to restrict MHV3 growth correlated with the diminished virus binding and virus receptor gene expression, leading us to suggest that these experimental observations reflect the contribution to the in vivo resistance expressed by these mice following experimental virus infection (7).…”

Section: Resultsmentioning

confidence: 86%

“…Selected up-or down-regulated genes, listed in Tables 2 and 3, respectively, may serve as a basis for evaluating physiological changes promoted by IFN-γ in macrophages. Table 4 presents a list of 42 differentially expressed genes and their function in macrophage biology, as indicated by recent publications (7,. One can observe modulation of genes coding for proteins involved in enzymatic reactions such as adenosine monophosphate deaminase, pyruvate kinase, acetoacetyl-CoA synthetase, TNF-α converting enzyme, serine protease inhibitor, or involved in the control of nucleic acid synthesis and transport such as DNA ligase, RNA polymerase II, zinc finger protein or protein synthesis, transport Data for gene expression profiling in macrophages from A/J or BALB/c mice activated or not with IFN-γ in vitro (control, C) and IFN-γ-activated macrophage cultures (IFN-γ).…”

Section: Resultsmentioning

confidence: 99%

“…For virus receptor expression, total cellular RNA was extracted from IFN-γ-activated macrophage cultures and reverse transcribed and the cDNAs were submitted to the polymerase chain reaction containing specific primers. Samples were then submitted to agarose gel electrophoresis for visualization (7).…”

Section: Mhv3 Replication and Receptor Expressionmentioning

confidence: 99%

“…Studying the molecular basis of the virus resistance induced by IFN-γ in macrophages, we have recently shown that down-regulation of a viral receptor gene with consequences on the gene product synthesis may be implicated in the resistance shown by A/ J mice (7). In a previous study, by means of proteomic analysis of proteins extracted from A/J or BALB/c macrophages, we were able to tag several gene products that were synthesized at elevated or diminished levels (8), indicating that macrophages from resistant and susceptible strains behave differently at the molecular level upon IFN-γ activation.…”

Section: Introductionmentioning

confidence: 99%

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Gene expression in IFN-gamma-activated murine macrophages

Pereira

Modolell

Frey³

et al. 2004

Braz J Med Biol Res

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Macrophages are critical for natural immunity and play a central role in specific acquired immunity. The IFN-γ activation of macrophages derived from A/J or BALB/c mice yielded two different patterns of antiviral state in murine hepatitis virus 3 infection, which were related to a down-regulation of the main virus receptor. Using cDNA hybridization to evaluate mRNA accumulation in the cells, we were able to identify several genes that are differently up-or down-regulated by IFN-γ in A/J (267 and 266 genes, respectively, up-and down-regulated) or BALB/c (297 and 58 genes, respectively, up-and downregulated) mouse macrophages. Macrophages from mice with different genetic backgrounds behave differently at the molecular level and comparison of the patterns of non-activated and IFN-γ-activated A/J or BALB/c mouse macrophages revealed, for instance, an up-regulation and a down-regulation of genes coding for biological functions such as enzymatic reactions, nucleic acid synthesis and transport, protein synthesis, transport and metabolism, cytoskeleton arrangement and extracellular matrix, phagocytosis, resistance and susceptibility to infection and tumors, inflammation, and cell differentiation or activation. The present data are reported in order to facilitate future correlation of proteomic/transcriptomic findings as well as of results obtained from a classical approach for the understanding of biological phenomena. The possible implication of the role of some of the gene products relevant to macrophage biology can now be further scrutinized. In this respect, a down-regulation of the main murine hepatitis virus 3 receptor gene was detected only in IFN-γ-activated macrophages of resistant mice.

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Section: Introductionsupporting

confidence: 86%

Section: Resultsmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Mhv3 Replication and Receptor Expressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Gene expression in IFN-gamma-activated murine macrophages

Pereira

Modolell

Frey³

et al. 2004

Braz J Med Biol Res

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Association between nitric oxide synthesis and vaccination-acquired resistance to murine hepatitis virus by spf mice

Tsuhako

Augusto

Linares

et al. 2006

Free Radical Biology and Medicine

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Murine hepatitis virus strain 3 (MHV-3) produces a strain-dependent pattern of disease, with A/J and BALB/c mice being considered models of resistance and susceptibility, respectively. A role for nitric oxide in controlling infection remains debatable; thus, we monitored nitric oxide levels in blood and liver of immunized and nonimmunized spf mice during infection by electron paramagnetic resonance. In parallel, liver histology, virus titers, and plasma alanine aminotransferase (ALT) activity were monitored. Nitric oxide synthesis was barely detectable in BALB/c mice, which showed a progressive increase in virus titers and ALT activity. These animals died with a shorter survival time than A/J mice. The latter displayed a less severe infection and presented detectable levels of nitric oxide as nitrosyl complexes in blood and liver at 72 hpi. Immunized mice from both strains became resistant to MHV-3 and showed comparable levels of nitrosyl complexes in blood and liver at an early time (24 hpi). Thereafter, nitric oxide levels decreased but remained detectable in blood up to 96 hpi. Immunized mice were capable of clearing the virus and clearance was inhibited by administration of a nitric oxide synthase inhibitor. Overall, the results support a role for nitric oxide in controlling MHV-3 infection.

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Arginine metabolism during macrophage autocrine activation and infection with mouse hepatitis virus 3

et al. 2004

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In contrast to BALB/c mouse macrophages (Mphi), Mphi from the A/J mouse strain, upon activation by exogenous interferon gamma (IFNgamma), develop an anti-mouse hepatitis virus 3 (MHV3) state which correlates with resistance to virus infection. To investigate the autocrine activation of BALB/c and A/J Mphi, we activated them with interleukin-12 (IL-12) and/or IL-18, and quantified IFNgamma production, the anti-MHV3 state and arginine metabolism. Synergistic activation by IL-12/IL-18 induced the expression of the IFNgamma gene in Mphi from both mouse strains. In bone marrow (BM) or peritoneal (P) Mphi of specific pathogen-free (spf) mice of both strains, IFNgamma synthesis occurred only with a synergistic IL-12/IL-18 activation and showed increasing levels from 24 to 72 h of activation. In contrast, when non-spf mice were used in the assay, their PMphi synthesized higher IFNgamma levels upon activation with only IL-12 or only IL-18 or both. The BALB/c Mphi were always capable of synthesizing higher amounts of IFNgamma than the A/J Mphi. An anti-MHV3 state was observed only in A/J Mphi upon activation with IL-12/IL-18 or IFNgamma regardless of their origin from the peritoneum or bone marrow. Arginine metabolism in activated and/or virus infected BMMphi was investigated through nitric oxide (NO) and arginase induction as well as the consumption of arginine and synthesis of citrulline, ornithine and spermine. The results showed that both BALB/c and A/J BMMphi populations released NO only after activation with IL-12/IL-18 or IFNgamma. Arginase was not induced in BMMphi from both strains by IL-12/IL-18 or IFNgamma but only by IL-4/IL-10. Higher arginine consumption was observed in BMMphi from both strains upon activation with IL-4 or IFNgamma which further increased, in this case, when the cells were infected with MHV3. As a consequence of nitric oxide synthase synthesis and arginine consumption in IFNgamma activated BMMphi, we observed a higher synthesis of citrulline. High levels of ornithine were induced only upon IL-4 activation. Polyamine synthesis was higher in A/J BMMphi than in BALB/c ones, which correlated with the slightly lower levels of ornithine observed. Upon infection with MHV3, we observed a higher synthesis of spermine. IL-12/IL-18 or IFNgamma activation, mainly in MHV3 infected cells, led to a decreased synthesis of polyamines, notably spermine, only in A/J BMMphi. Difluoromethylornithine treatment, which leads to inhibition of polyamine synthesis, induced a decreased MHV3 multiplication in both BALB/c and A/J BMMphi. Altogether these data show the relevance of IFNgamma, from the autocrine or paracrine pathway, and arginine metabolism for the control of MHV3 replication in Mphi of a resistant mouse strain.

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Down-regulation of Bgp1a Viral Receptor by Interferon-γ Is Related to the Antiviral State and Resistance to Mouse Hepatitis Virus 3 Infection

Cited by 12 publications

References 33 publications

Gene expression in IFN-gamma-activated murine macrophages

Gene expression in IFN-gamma-activated murine macrophages

Association between nitric oxide synthesis and vaccination-acquired resistance to murine hepatitis virus by spf mice

Arginine metabolism during macrophage autocrine activation and infection with mouse hepatitis virus 3

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