IL-10 Potentiates Differentiation of Human Induced Regulatory T Cells via STAT3 and Foxo1

Hsu, Peter; Santner-Nanan, Brigitte; Hu, Mingtao; Skarratt, Kristen K.; Lee, Cheng Hiang; Stormon, Michael; Wong, Melanie; Fuller, Stephen J.; Nanan, Ralph

doi:10.4049/jimmunol.1402898

Cited by 230 publications

(189 citation statements)

References 55 publications

Supporting

Mentioning

175

Contrasting

Order By: Relevance

“…Previous reports have shown that FoxO1 and Stat3 antagonize each other in the regulation of T-cell function (34,35) and leptin signaling transduction (36,37). We were thus prompted to evaluate the role of FoxO1 during the process of β-cell EMT in this CPRD model, because the inflammatory environment in the PDL-tail presumably induces significant local cell stress.…”

Section: Resultsmentioning

confidence: 99%

SMAD3/Stat3 Signaling Mediates β-Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis–Related Diabetes

et al. 2017

View full text Add to dashboard Cite

Many patients with chronic pancreatitis develop diabetes (chronic pancreatitis–related diabetes [CPRD]) through an undetermined mechanism. Here we used long-term partial pancreatic duct ligation (PDL) as a model to study CPRD. We found that long-term PDL induced significant β-cell dedifferentiation, followed by a time-dependent decrease in functional β-cell mass—all specifically in the ligated tail portion of the pancreas (PDL-tail). High levels of transforming growth factor β1 (TGFβ1) were detected in the PDL-tail and were mainly produced by M2 macrophages at the early stage and by activated myofibroblasts at the later stage. Loss of β-cell mass was then found to result from TGFβ1-triggered epithelial-mesenchymal transition (EMT) by β-cells, rather than resulting directly from β-cell apoptosis. Mechanistically, TGFβ1-treated β-cells activated expression of the EMT regulator gene Snail in a SMAD3/Stat3-dependent manner. Moreover, forced expression of forkhead box protein O1 (FoxO1), an antagonist for activated Stat3, specifically in β-cells ameliorated β-cell EMT and β-cell loss and prevented the onset of diabetes in mice undergoing PDL. Together, our data suggest that chronic pancreatitis may trigger TGFβ1-mediated β-cell EMT to lead to CPRD, which could substantially be prevented by sustained expression of FoxO1 in β-cells.

show abstract

Section: Resultsmentioning

confidence: 99%

SMAD3/Stat3 Signaling Mediates β-Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis–Related Diabetes

et al. 2017

View full text Add to dashboard Cite

show abstract

“…In the context of T helper differentiation, the T follicular helper (T FH ) subset requires engagement of the costimulatory receptor, ICOS, which activates PI3K/AKT to suppress Foxo1-dependent gene expression (Rolf et al, 2010; Stone et al, 2015). Foxo1 also plays a role in the differentiation of murine and human regulatory T cells (Tregs) (Hsu et al, 2015; Kerdiles et al, 2010); notably, Foxo1 activity must be finely tuned to preserve Treg trafficking and function (Luo et al, 2016). The decision of CD8 + T cells to adopt effector or memory gene expression programs also depends on the balance of AKT and FOXO activity (Hess Michelini et al, 2013; Macintyre et al, 2011).…”

Section: Pi3k In Innate and Adaptive Immunitymentioning

confidence: 99%

The PI3K Pathway in Human Disease

Fruman

Chiu

Hopkins

et al. 2017

Cell

1,967

1,658

View full text Add to dashboard Cite

Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers, and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.

show abstract

“…Further studies, including the suppression assay of Foxp3þ Tregs or the numbers of FoxP3þ Tregs in the spleen in our model, might be needed to explain this discrepancy. 27,[29][30][31] In conclusion, we have demonstrated that BG is capable of stimulating IL-10-producing CD4þ T cells, and suppressing the Th2 response in draining LNs and conjunctival eosinophil infiltration, demonstrating the therapeutic potential of topical BG for AC. Although further studies are required to understand the basis of the findings, our results should add new insight into the therapeutic potential of BG for allergic diseases including asthma or atopic dermatitis.…”

Section: Discussionmentioning

confidence: 95%

Topical Administration of β-1,3-Glucan to Modulate Allergic Conjunctivitis in a Murine Model

Lee

Kwon

Joo

2016

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

Citation: Lee HS, Kwon JY, Joo C-K. Topical administration of b-1,3-glucan to modulate allergic conjunctivitis in a murine model. Invest Ophthalmol Vis Sci. 2016;57:135257: -136057: . DOI:10.1167 PURPOSE. Recent studies on b-1,3-glucan (BG), a cell wall component of a variety of fungi, yeasts, and bacteria, demonstrated that it affects the balance of Th1/Th2 immune responses. We therefore determined whether topical application of BG modulates ocular allergy in a murine model. METHODS.We sensitized 7-to 8-week-old BALB/c mice once with ovalbumin (OVA) and aluminum hydroxide via intraperitoneal injection. Mice were rested for 2 weeks and then challenged by instillation of OVA eye drops once daily for 13 days. We administered BG eye drops 5 minutes after OVA challenge once daily. Clinical signs were measured, the infiltration of eosinophils and mast cells into conjunctiva was assessed with flow cytometry, and the serum levels of OVA-specific IgE production and Th2 cytokines after in vitro stimulation of T cells in draining lymph nodes (LN) were determined. RESULTS.Mice treated with BG showed attenuated allergic conjunctivitis, as indicated by clinical signs and decreased production of serum OVA-specific IgE. In addition, BG treatment led to decreased infiltration of CD45þ immune cells, eosinophils, and mast cells into the conjunctiva, compared with the mice treated with vehicle alone (control mice). Administration of BG suppressed Th2 cytokine production in in vitro T-cell assays partially through the induction of interleukin (IL)-10-producing CD4 T cells in draining LNs.CONCLUSIONS. Taken together, these results suggest that BG is capable of stimulating IL-10-producing CD4þ T cells and suppressing both the Th2 response in draining LNs and conjunctival eosinophil infiltration. We therefore demonstrated the therapeutic potential of topical BG administration for allergic conjunctivitis.

show abstract

IL-10 Potentiates Differentiation of Human Induced Regulatory T Cells via STAT3 and Foxo1

Cited by 230 publications

References 55 publications

SMAD3/Stat3 Signaling Mediates β-Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis–Related Diabetes

SMAD3/Stat3 Signaling Mediates β-Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis–Related Diabetes

The PI3K Pathway in Human Disease

Topical Administration of β-1,3-Glucan to Modulate Allergic Conjunctivitis in a Murine Model

Contact Info

Product

Resources

About