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Title: Transcriptional regulation of type I interferon responses of myeloid antigen presenting cells
Authors: Sin, Wei Xiang
Keywords: DRNTU::Science::Biological sciences
Issue Date: 2016
Source: Sin, W. X. (2016). Transcriptional regulation of type I interferon responses of myeloid antigen presenting cells. Doctoral thesis, Nanyang Technological University, Singapore.
Abstract: Macrophages, as crucial mediators of an innate immune response, exhibit functional plasticity by playing an essential role in both the initiation and resolution of inflammation. Production of the pro-inflammatory cytokine IL-1β, via caspase-11 activation during Gram-negative bacterial infections, and of the pro-regulatory cytokine IL-10, are dependent on signaling by the pleiotropic type I interferon (IFN), IFN-β. The transcription factor IRF7 is thought to be primarily involved in the regulation of type I IFN responses in viral infections. Here we show IRF7 also regulates IFN-β responses to bacterial lipopolysaccharide in bone marrow-derived macrophages (BMDMs) but not in bone marrow-derived dendritic cells (BMDCs). In BMDMs, IRF7 co-operated with IRF3 to elicit robust IFN-β responses to endotoxin exposure, whereas BMDCs depended on IRF3 alone to mediate this response and thus displayed blunted IFN-β expression. IRF7-mediated IFN-β production is necessary for efficient expression of pro-caspase-11 in BMDMs. Accordingly, Irf7–/– mice exhibited substantially reduced serum levels of type I IFN and IL-1β, and were resistant to lethal endotoxin shock. We found that, unlike BMDCs, BMDMs constitutively expressed IRF7 protein. The high basal IRF7 expression in steady-state BMDMs was maintained by constitutive IFN-β signaling, which was in turn dependent on tonic signaling by IL-27p28. Accordingly, in response to TLR4 ligation, BMDMs but not BMDCs depended on IL-27p28 to induce IFN-β synthesis. IL-27p28-mediated IFN-β production, and not IL-27 cytokine itself, is required to restrain inflammatory responses to endotoxin exposure, since BMDMs deficient in IL-27p28 displayed reduced IL-10 synthesis and impaired STAT3-mediated anti-inflammatory responses, which were reversed by addition of exogenous IFN-β. Our data identified a tonic IL-27p28-IFN-β signaling axis as a novel cell type-specific regulator of TLR4-mediated IFN-β induction through the regulation of constitutively expressed IRF7.
DOI: 10.32657/10356/66024
Fulltext Permission: open
Fulltext Availability: With Fulltext
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