Article

Rig-I-/- mice develop colitis associated with downregulation of G alpha i2.

Department of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Cell Research (Impact Factor: 11.98). 11/2007; 17(10):858-68. DOI: 10.1038/cr.2007.81
Source: PubMed

ABSTRACT RIG-I (retinoid acid-inducible gene-I), a putative RNA helicase with a cytoplasmic caspase-recruitment domain (CARD), was identified as a pattern-recognition receptor (PRR) that mediates antiviral immunity by inducing type I interferon production. To further study the biological function of RIG-I, we generated Rig-I(-/-) mice through homologous recombination, taking a different strategy to the previously reported strategy. Our Rig-I(-/-) mice are viable and fertile. Histological analysis shows that Rig-I(-/-) mice develop a colitis-like phenotype and increased susceptibility to dextran sulfate sodium-induced colitis. Accordingly, the size and number of Peyer's patches dramatically decreased in mutant mice. The peripheral T-cell subsets in mutant mice are characterized by an increase in effector T cells and a decrease in naive T cells, indicating an important role for Rig-I in the regulation of T-cell activation. It was further found that Rig-I deficiency leads to the downregulation of G protein alpha i2 subunit (G alpha i2) in various tissues, including T and B lymphocytes. By contrast, upregulation of Rig-I in NB4 cells that are treated with ATRA is accompanied by elevated G alpha i2 expression. Moreover, G alpha i2 promoter activity is increased in co-transfected NIH3T3 cells in a Rig-I dose-dependent manner. All these findings suggest that Rig-I has crucial roles in the regulation of G alpha i2 expression and T-cell activation. The development of colitis may be, at least in part, associated with downregulation of G alpha i2 and disturbed T-cell homeostasis.

0 Bookmarks
 · 
157 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Previously, we observed that mir-155 is induced during dendritic cell (DC) differentiation. We now demon-strated convincing evidence indicating that mir-155 promotes DC maturation and regulates its capacity for antigen presentation and induction of alloreactive T cell activation. Interestingly, the induction of miR-155 expression in DCs is dependent on the TLR4/Myd88/NF-κB signaling. Our mechanistic studies further revealed that SOCS1 is a direct target for mir-155, and by binding to its 3'UTR, mir-155 is likely to affect SOCS1 translation. Suppression of mir-155 expression in DCs significantly attenuated LPS-induced DC maturation along with reduced capability to stimulate allogeneic T cell proliferation. As a result, administration of antagomiR-155 provided protection for cardiac allografts from rejection. Together, our data support that suppression of miR-155 in DCs could be a viable therapeutic strategy for prevention and treatment of allograft rejection in clinical setting of transplantation.
    International Journal of Clinical and Experimental Medicine 01/2014; 7(11):4572-83. · 1.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Influenza A virus (IAV) triggers a contagious respiratory disease that can cause considerable morbidity and mortality. Using an in vitro approach, we previously demonstrated that the pattern recognition receptor RIG-I plays a key role in IAV-mediated immune response. However, the importance of RIG-I signaling in vivo has not been thoroughly examined because of the lack of an appropriate mouse models. To circumvent this issue, we generated a new transgenic mouse overexpressing LGP2 (LGP2 TG), a major regulator of the RIG-I signaling pathway. The time-course of several parameters was compared in infected WT and LGP2 TG mice. We found that LGP2 TG animals display significantly reduced inflammatory mediators and a lower leukocyte infiltration into the bronchoalveolar airspace. More importantly, mice overexpressing LGP2 had a significant survival advantage. Hence, our in vivo study reveals that LGP2 is a major downregulator of the IAV-triggered detrimental inflammatory response.
    The Journal of Infectious Diseases 02/2014; · 5.85 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Enteropathogenic Escherichia coli (EPEC) primarily infects children in developing countries and causes diarrhea that can be deadly. EPEC pathogenesis occurs through Type III secretion system (T3SS)-mediated injection of effectors into intestinal epithelial cells (IECs); these effectors alter actin dynamics, modulate the immune response and disrupt tight junction (TJ) integrity. The resulting compromised barrier function and increased gastrointestinal (GI) permeability may be responsible for the clinical symptoms of infection. Type I interferon (IFN) mediates anti-inflammatory activities and serves essential functions in intestinal immunity and homeostasis, however its role in the immune response to enteric pathogens such as EPEC, and its impact on IEC barrier function, have not been examined. Here we report that IFNβ is induced following EPEC infection and regulates IEC TJ proteins to maintain barrier function. The EPEC T3SS effector NleD counteracts this protective activity by inhibiting IFNβ induction and enhancing tumor necrosis factor-α to promote barrier disruption. The endoribonuclease RNase-L is a key mediator of IFN induction and action that promotes TJ protein expression and IEC barrier integrity. EPEC infection inhibits RNase-L in a T3SS-dependent manner providing a mechanism by which EPEC evades IFN-induced antibacterial activities. This work identifies novel roles for IFNβ and RNase-L in IEC barrier functions that are targeted by EPEC effectors to escape host defense mechanisms and promote virulence. The IFN/RNase-L axis thus represents a potential therapeutic target for enteric infections and GI diseases involving compromised barrier function.
    Infection and immunity 04/2014; · 4.16 Impact Factor

Full-text (2 Sources)

Download
0 Downloads
Available from
Feb 11, 2015