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?-Arrestin-1 deficiency protects mice from experimental colitis.

ABSTRACT: ?-Arrestins are intracellular scaffolding proteins that modulate specific cell signaling pathways. Recent studies, in both cell culture and in vivo models, have demonstrated an important role for ?-arrestin-1 in inflammation. However, the role of ?-arrestin-1 in the pathogenesis of inflammatory bowel disease (IBD) is not known. Our goal was to investigate the role of ?-arrestin-1 in IBD using mouse models of colitis. To this end, we subjected wild-type (WT) and ?-arrestin-1 knockout (?-arr-1(-/-)) mice to colitis induced by trinitrobenzenesulfonic acid or dextran sulfate sodium and examined the clinical signs, gross pathology, and histopathology of the colon, as well as inflammatory components. The ?-arr-1(-/-) mice displayed significantly attenuated colitis, compared with WT mice, in both models. Consistent with the phenotypic observations, histological examination of the colon revealed attenuated disease pathology in the ?-arr-1(-/-) mice. Our results further demonstrate that ?-arr-1(-/-) mice are deficient in IL-6 expression in the colon, but have higher expression of the anti-inflammatory IL-10 family of cytokines. Our results also demonstrate diminished ERK and NF?B pathways in the colons of ?-arr-1(-/-) mice, compared with WT mice. Taken together, our results demonstrate that decreased IL-6 production and enhanced IL-10 and IL-22 production in ?-arrestin-1-deficient mice likely lead to attenuated gut inflammation.

SUBMITTER: Lee T

PROVIDER: S-EPMC3620400 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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β-Arrestin-1 deficiency protects mice from experimental colitis.

Lee Taehyung T Lee Eunhee E Irwin Regina R Lucas Peter C PC McCabe Laura R LR Parameswaran Narayanan N

The American journal of pathology 20130208 4

β-Arrestins are intracellular scaffolding proteins that modulate specific cell signaling pathways. Recent studies, in both cell culture and in vivo models, have demonstrated an important role for β-arrestin-1 in inflammation. However, the role of β-arrestin-1 in the pathogenesis of inflammatory bowel disease (IBD) is not known. Our goal was to investigate the role of β-arrestin-1 in IBD using mouse models of colitis. To this end, we subjected wild-type (WT) and β-arrestin-1 knockout (β-arr-1(-/- ...[more]

PMID: 23395087

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Project description:The endoribonuclease RNase-L is a type-I interferon (IFN)-regulated component of the innate immune response that functions in antiviral, antibacterial, and antiproliferative activities. RNase-L produces RNA agonists of RIG-I-like receptors, sensors of cytosolic pathogen-associated RNAs that induce cytokines including IFN-?. IFN-? and RIG-I-like receptors signaling mediate protective responses against experimental colitis and colitis-associated cancer and contribute to gastrointestinal homeostasis. Therefore, we investigated a role for RNase-L in murine colitis and colitis-associated cancer and its association with RIG-I-like receptors signaling in response to bacterial RNA.Colitis was induced in wild type-deficient and RNase-L-deficient mice (RNase-L?/?) by administration of dextran sulfate sodium (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM). Histological analysis and immunohistochemistry were performed on colon tissue to analyze immune cell infiltration and tissue damage after induction of colitis. Expression of cytokines was measured by quantitative real-time-PCR and ELISA.DSS-treated RNase-L?/? mice exhibited a significantly higher clinical score, delayed leukocyte infiltration, reduced expression of IFN-?, tumor necrosis factor ?, interleukin-1?, and interleukin-18 at early times post-DSS exposure, and increased mortality as compared with wild-type mice. DSS/AOM-treated RNase-L?/? mice displayed an increased tumor burden. Bacterial RNA triggered IFN-? production in an RNase-L-dependent manner and provided a potential mechanism by which RNase-L contributes to the gastrointestinal immune response to microbiota and protects against experimental colitis and colitis-associated cancer.RNase-L promotes the innate immune response to intestinal damage and ameliorates murine colitis and colitis-associated cancer. The RNase-L-dependent production of IFN-? stimulated by bacterial RNA may be a mechanism to protect against gastrointestinal inflammatory disease.

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?-Arrestin-1 deficiency protects mice from experimental colitis.

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β-Arrestin-1 deficiency protects mice from experimental colitis.

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