Prostaglandin E2 and SOCS1 have a role in intestinal immune tolerance

Abstract

Interleukin 10 (IL-10) and regulatory T cells (Tregs) maintain tolerance to intestinal microorganisms. However, Il10−/−Rag2−/− mice, which lack IL-10 and Tregs, remain healthy, suggesting the existence of other mechanisms of tolerance. Here, we identify suppressor of cytokine signalling 1 (SOCS1) as an essential mediator of immune tolerance in the intestine. Socs1−/−Rag2−/− mice develop severe colitis, which can be prevented by the reduction of microbiota and the transfer of IL-10-sufficient Tregs. Additionally, we find an essential role for prostaglandin E2 (PGE2) in the maintenance of tolerance within the intestine in the absence of Tregs. Socs1−/− dendritic cells are resistant to PGE2-mediated immunosuppression because of dysregulated cytokine signalling. Thus, we propose that SOCS1 and PGE2, potentially interacting together, act as an alternative intestinal tolerance mechanism distinct from IL-10 and Tregs.

A20 controls intestinal homeostasis through cell-specific activities

“…Histopathology was scored as described earlier 56 . Briefly, colitis scores were determined as averages of six histological parameters (goblet cell loss, crypt abscesses, mucosal hyperaemia, cellular infiltration in the lamina propria, mucosal elongation and epithelial erosion), with scores according to a scale as follows: 0, normal histology; 1, mild pathology for each histological parameter; 2, moderate pathology; and 3, severe pathology.…”

Histone 3 Lysine 9 (H3K9) Methyltransferase Recruitment to the Interleukin-2 (IL-2) Promoter Is a Mechanism of Suppression of IL-2 Transcription by the Transforming Growth Factor-β-Smad Pathway

“…For Western blotting, the immunoprecipitates or whole cell lysates were resolved through SDS-PAGE and transferred to Immobilon-P membranes (Millipore, Billerica, MA). The membranes were blotted with the indicated antibodies, and the bound antibodies were visualized with horseradish peroxidaseconjugated antibodies against rabbit or mouse IgG using Chemi-Lumi One L Western-blotting detection reagents (Nacalai Tesque) as described previously (24).…”

The Pharmacological and Physiological Role of Multidrug-Resistant Protein 4

“…The continuous elevated extracellular PGE 2 can shift the tumor microenvironment from antitumor to immunosuppressive responses, resulting in escape of tumor cells from effective immunosurveillance (Wang and DuBois, 2013). It has been shown that PGE 2 can downregulate tumor immunity through inhibiting dendritic cell (DC) differentiation and switching the function of DCs from induction of immunity to T-cell tolerance (Chinen et al, 2011); inhibiting CD8 1 T-cell proliferation and activity (Ganapathy et al, 2000); the inhibition of mature B-cell proliferation and induction of immature B-cell apoptosis (Shimozato and Kincade, 1999); downregulation of antitumor TH1 cytokines and upregulation of immunosuppressive TH2 cytokines (Fabricius et al, 2010); and inducing myeloid-derived suppressor cell differentiation (Sinha et al, 2007). More importantly, PGE 2 can bind to the EP2/4 receptor and activate the downstream cascades, leading to epithelium stem cell transition, metastasis, antiapoptosis, and proliferation (Rao et al, 2007;Rasmuson et al, 2012;Charo et al, 2013).…”