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The programmed death-1 and interleukin-10 pathways play a down-modulatory role in LP-BM5 retrovirus-induced murine immunodeficiency syndrome.

ABSTRACT: Pathology due to the immune system's response to viral infections often represents a delicate balance between inhibition of viral pathogenesis and regulation of protective immunity. In susceptible C57BL/6 (B6) mice, the murine retroviral isolate LP-BM5 induces splenomegaly, hypergammaglobulinemia, profound B- and T-cell immunodeficiency, and increased susceptibility to opportunistic pathogens and terminal B-cell lymphomas. Here, we report that B6.PD-1 (programmed death-1) and B6.IL-10 knockout mice are substantially more susceptible to LP-BM5-induced disease than wild-type B6 mice. LP-BM5-infected B6.PD-1(-/-) mice developed more severe splenomegaly, hypergammaglobulinemia, and immunodeficiency than infected B6 mice: PD-1(-/-) mice are more susceptible to lower doses of LP-BM5 and show more exaggerated disease early postinfection. LP-BM5-infected B6.IL-10(-/-) mice also develop exaggerated LP-BM5-induced disease, compared to B6 mice, without a significant change in the retroviral load. By reciprocal reconstitution experiments, comparing wild-type versus PD-1(-/-) sources of the requisite cells for LP-BM5 pathogenesis-CD4 T and B cells, PD-1(+) B cells appear to be crucial in the normal limitation of LP-BM5-induced disease in B6 mice. Also, infected B6 mice have increased CD11b(+) spleen cells that express interleukin-10 (IL-10). However, PD-1(-/-) mice, though showing an even greater expansion of CD11b(+) cells after LP-BM5 inoculation, did not show an equivalent increase in IL-10-producing cells. Thus, it appears that PD-1/PD-L interactions and IL-10 are primarily important in moderating the effects of LP-BM5-induced disease in B6 mice.

SUBMITTER: Green KA

PROVIDER: S-EPMC2258922 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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The programmed death-1 and interleukin-10 pathways play a down-modulatory role in LP-BM5 retrovirus-induced murine immunodeficiency syndrome.

Green Kathy A KA Okazaki Taku T Honjo Tasuku T Cook W James WJ Green William R WR

Journal of virology 20071219 5

Pathology due to the immune system's response to viral infections often represents a delicate balance between inhibition of viral pathogenesis and regulation of protective immunity. In susceptible C57BL/6 (B6) mice, the murine retroviral isolate LP-BM5 induces splenomegaly, hypergammaglobulinemia, profound B- and T-cell immunodeficiency, and increased susceptibility to opportunistic pathogens and terminal B-cell lymphomas. Here, we report that B6.PD-1 (programmed death-1) and B6.IL-10 knockout m ...[more]

PMID: 18094175

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Project description:BackgroundMicroRNAs (miRNAs) play crucial roles in regulating eukaryotic gene expression. Recent studies indicated that aberrantly expressed miRNAs are involved in the pathogenesis of ankylosing spondylitis (AS). Indeed, hsa-miR-495-3p (miR-495) has been reported as an anti-oncogene in different cancers. However, the role of miR-495 in AS is still unknown.MethodsIn this study, quantitative real-time polymerase chain reaction (PCR) was used to detect the expression of miR-495 in the peripheral blood mononuclear cells (PBMCs), whole blood, and serum of patients with AS. Bisulfite-specific PCR sequencing and methylated DNA immunoprecipitation were used to detect the methylation in the promoter region of miR-495. To determine the influence of miR-495 expression on the target gene, programmed cell death 10 (PDCD10), dual luciferase reporter assays together with an adenoviral vector containing the miR-495 locus were used. Receiver operating characteristic (ROC) curves were used to evaluate the efficacy of miR-495 as a diagnostic biomarker of AS. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and western blotting were used to explore the potential role of miR-495 in AS pathogenesis and the mechanism by which it facilitates AS pathogenesis.ResultsmiR-495 is down-regulated and the promoter region of miR-495 is highly methylated in AS. The expression of miR-495 is negatively associated with PDCD10 expression in both patients with AS and healthy controls. Further experiments showed that PDCD10 can be targeted by miR-495. The ROC curves of miR-495 suggested that it is a very specific and sensitive biomarker for AS diagnosis. Bioinformatics analysis and signal pathway studies indicated that miR-495 can down-regulate ?-catenin and transforming growth factor-?1.ConclusionsOur studies indicated that down-regulation of miR-495 can be used as a potential molecular marker for the diagnosis and treatment of AS, thus providing new insights into the role of miRNAs in AS pathology.

Dataset Information

The programmed death-1 and interleukin-10 pathways play a down-modulatory role in LP-BM5 retrovirus-induced murine immunodeficiency syndrome.

Publications

The programmed death-1 and interleukin-10 pathways play a down-modulatory role in LP-BM5 retrovirus-induced murine immunodeficiency syndrome.

Similar Datasets

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