Dataset Information

Species Specificity of Type III Interferon Activity and Development of a Sensitive Luciferase-Based Bioassay for Quantitation of Mouse Interferon-?.

ABSTRACT: The type III interferon (IFN-?) family includes 4 IFN-? subtypes in man. In the mouse, only the genes coding for IFN-?2 and -?3 are present. Unlike mouse and human type I IFNs (IFN-?/?), which exhibit strong species specificity, type III IFNs were reported to act in a cross-specific manner. We reexamined the cross-specificity and observed that mouse and human IFN-? exhibit some species specificity, although much less than type I IFNs. Mouse IFN-?3 displayed clear species specificity, being 25-fold less active in human cells than the closely related mouse IFN-?2. This specificity likely depends on amino acids in ? helices A and F that diverged from other IFN-? sequences. Human IFN-?4, in contrast, retained high activity in mouse cells. We next developed a firefly luciferase-based reporter cell line, named Fawa-?-luc, to detect IFN-? in biological fluids with high specificity and sensitivity. Fawa-?-luc cells, derived from mouse epithelial cells that are responsive to IFN-?, were made nonresponsive to type I IFNs by inactivation of the Ifnar2 gene and strongly responsive to IFN-? by overexpression of the mouse IFNLR1. This bioassay was as sensitive as a commercially available enzyme-linked immunosorbent assay in detecting mouse IFN-? in cell culture supernatant, as well as in serum and bronchoalveolar lavage samples of virus-infected mice. The assay also enabled the sensitive detection of human IFN-? activity, including that of the divergent IFN-?4 with a bias, however, due to variable activity of IFN-? subtypes.

SUBMITTER: Jacobs S

PROVIDER: S-EPMC6249671 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Publications

Species Specificity of Type III Interferon Activity and Development of a Sensitive Luciferase-Based Bioassay for Quantitation of Mouse Interferon-λ.

Jacobs Sophie S Wavreil Fanny F Schepens Bert B Gad Hans Henrik HH Hartmann Rune R Rocha-Pereira Joana J Neyts Johan J Saelens Xavier X Michiels Thomas T

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20181018 11

The type III interferon (IFN-λ) family includes 4 IFN-λ subtypes in man. In the mouse, only the genes coding for IFN-λ2 and -λ3 are present. Unlike mouse and human type I IFNs (IFN-α/β), which exhibit strong species specificity, type III IFNs were reported to act in a cross-specific manner. We reexamined the cross-specificity and observed that mouse and human IFN-λ exhibit some species specificity, although much less than type I IFNs. Mouse IFN-λ3 displayed clear species specificity, being 25-fo ...[more]

PMID: 30335553

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Project description:The Type I Interferon family of cytokines all act through the same cell surface receptor and induce phosphorylation of the same subset of response regulators of the STAT family. Despite their shared receptor, different Type I Interferons have different functions during immune response to infection. In particular, they differ in the potency of their induced anti-viral and anti-proliferative responses in target cells. It remains not fully understood how these functional differences can arise in a ligand-specific manner both at the level of STAT phosphorylation and the downstream function. We use a minimal computational model of Type I Interferon signaling, focusing on Interferon-α and Interferon-β. We validate the model with quantitative experimental data to identify the key determinants of specificity and functional plasticity in Type I Interferon signaling. We investigate different mechanisms of signal discrimination, and how multiple system components such as binding affinity, receptor expression levels and their variability, receptor internalization, short-term negative feedback by SOCS1 protein, and differential receptor expression play together to ensure ligand specificity on the level of STAT phosphorylation. Based on these results, we propose phenomenological functional mappings from STAT activation to downstream anti-viral and anti-proliferative activity to investigate differential signal processing steps downstream of STAT phosphorylation. We find that the negative feedback by the protein USP18, which enhances differences in signaling between Interferons via ligand-dependent refractoriness, can give rise to functional plasticity in Interferon-α and Interferon-β signaling, and explore other factors that control functional plasticity. Beyond Type I Interferon signaling, our results have a broad applicability to questions of signaling specificity and functional plasticity in signaling systems with multiple ligands acting through a bottleneck of a small number of shared receptors.

Dataset Information

Species Specificity of Type III Interferon Activity and Development of a Sensitive Luciferase-Based Bioassay for Quantitation of Mouse Interferon-?.

Publications

Species Specificity of Type III Interferon Activity and Development of a Sensitive Luciferase-Based Bioassay for Quantitation of Mouse Interferon-λ.

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