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Type I Interferons Control Proliferation and Function of the Intestinal Epithelium.

ABSTRACT: Wnt pathway-driven proliferation and renewal of the intestinal epithelium must be tightly controlled to prevent development of cancer and barrier dysfunction. Although type I interferons (IFN) produced in the gut under the influence of microbiota are known for their antiproliferative effects, the role of these cytokines in regulating intestinal epithelial cell renewal is largely unknown. Here we report a novel role for IFN in the context of intestinal knockout of casein kinase 1? (CK1?), which controls the ubiquitination and degradation of both ?-catenin and the IFNAR1 chain of the IFN receptor. Ablation of CK1? leads to the activation of both ?-catenin and IFN pathways and prevents the unlimited proliferation of intestinal epithelial cells despite constitutive ?-catenin activity. IFN signaling contributes to the activation of the p53 pathway and the appearance of apoptotic and senescence markers in the CK1?-deficient gut. Concurrent genetic ablation of CK1? and IFNAR1 leads to intestinal hyperplasia, robust attenuation of apoptosis, and rapid and lethal loss of barrier function. These data indicate that IFN play an important role in controlling the proliferation and function of the intestinal epithelium in the context of ?-catenin activation.

SUBMITTER: Katlinskaya YV

PROVIDER: S-EPMC4800802 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Type I Interferons Control Proliferation and Function of the Intestinal Epithelium.

Katlinskaya Yuliya V YV Katlinski Kanstantsin V KV Lasri Audrey A Li Ning N Beiting Daniel P DP Durham Amy C AC Yang Ting T Pikarsky Eli E Lengner Christopher J CJ Johnson F Brad FB Ben-Neriah Yinon Y Fuchs Serge Y SY

Molecular and cellular biology 20160125 7

Wnt pathway-driven proliferation and renewal of the intestinal epithelium must be tightly controlled to prevent development of cancer and barrier dysfunction. Although type I interferons (IFN) produced in the gut under the influence of microbiota are known for their antiproliferative effects, the role of these cytokines in regulating intestinal epithelial cell renewal is largely unknown. Here we report a novel role for IFN in the context of intestinal knockout of casein kinase 1α (CK1α), which c ...[more]

PMID: 26811327

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Project description:Type I (IFN-α/β) and type III (IFN-λ) interferons (IFNs) exert shared antiviral activities through distinct receptors. However, their relative importance for antiviral protection of different organ systems against specific viruses remains to be fully explored. We used mouse strains deficient in type-specific IFN signaling, STAT1 and Rag2 to dissect distinct and overlapping contributions of type I and type III IFNs to protection against homologous murine (EW-RV strain) and heterologous (non-murine) simian (RRV strain) rotavirus infections in suckling mice. Experiments demonstrated that murine EW-RV is insensitive to the action of both types of IFNs, and that timely viral clearance depends upon adaptive immune responses. In contrast, both type I and type III IFNs can control replication of the heterologous simian RRV in the gastrointestinal (GI) tract, and they cooperate to limit extra-intestinal simian RRV replication. Surprisingly, intestinal epithelial cells were sensitive to both IFN types in neonatal mice, although their responsiveness to type I, but not type III IFNs, diminished in adult mice, revealing an unexpected age-dependent change in specific contribution of type I versus type III IFNs to antiviral defenses in the GI tract. Transcriptional analysis revealed that intestinal antiviral responses to RV are triggered through either type of IFN receptor, and are greatly diminished when receptors for both IFN types are lacking. These results also demonstrate a murine host-specific resistance to IFN-mediated antiviral effects by murine EW-RV, but the retention of host efficacy through the cooperative action by type I and type III IFNs in restricting heterologous simian RRV growth and systemic replication in suckling mice. Collectively, our findings revealed a well-orchestrated spatial and temporal tuning of innate antiviral responses in the intestinal tract where two types of IFNs through distinct patterns of their expression and distinct but overlapping sets of target cells coordinately regulate antiviral defenses against heterologous or homologous rotaviruses with substantially different effectiveness.

Dataset Information

Type I Interferons Control Proliferation and Function of the Intestinal Epithelium.

Publications

Type I Interferons Control Proliferation and Function of the Intestinal Epithelium.

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