TRPV1 is a Ca2+-permeable channel mostly studied as a pain receptor in sensory neurons. However, its role in other cell types is poorly understood. Here, we demonstrate that TRPV1 is functionally expressed in CD4+ T cells where it acts as a non-store-operated Ca2+ channel and contributes to T cell receptor (TCR)-induced Ca2+ influx, TCR signaling and T cell activation. In models of T cell-mediated colitis, TRPV1 promotes colitogenic T cell responses and intestinal inflammation. Furthermore, genetic and pharmacological inhibition of TRPV1 in human CD4+ T cells recapitulates the phenotype of murine Trpv1−/− CD4+ T cells. These findings suggest that TRPV1 inhibition could represent a new therapeutic strategy to restrain proinflammatory T cell responses.

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Macrophage activation by the proinflammatory cytokine interferon-␥ (IFN-␥[Keywords: Mitochondria; macrophages; Listeria monocytogenes; oxidative metabolism; reactive oxygen species] Supplemental material is available at http://www.genesdev.org.

A hallmark of rheumatoid arthritis is the formation of an aggressive, tumor-like structure called pannus that erodes the joint. A major cellular component of the pannus is the fibroblast-like synoviocyte (FLS), whose morphology strikingly resembles that of a transformed cell, but underlying mechanisms of this ''transformation'' are not known. Here, using animal models of rheumatoid arthritis, we show that arthritic FLS contain a substantial (>30%) fraction of bone marrow-derived precursors that can differentiate in vitro into various mesenchymal cell types, but inflammation prevents the multilineage differentiation. We show that the transcription factor NF-B plays the key role in the repression of osteogenic and adipogenic differentiation of arthritic FLS. Furthermore, we show that specific activation of NF-B profoundly enhances proliferation, motility, and matrix-degrading activity of FLS. We thus propose that arthritic FLS are mesenchymal stem cells whose differentiation is arrested at early stages of differentiation by activation of NF-B.fibroblast-like synoviocytes ͉ mesenchymal stem cell ͉ rheumatoid arthritis

Tumor hypoxia, the "Achilles heel" of current cancer therapies,i si ndispensable to drug resistance and poor therapeutic outcomes especially for radiotherapy. Here we propose an in situ catalytic oxygenation strategy in tumor using porphyrinic metal-organic framework (MOF)-gold nanoparticles (AuNPs) nanohybrid as atherapeutic platform to achieve O 2 -evolving chemoradiotherapy. The AuNPs decorated on the surface of MOF effectively stabilize the nanocomposite and serve as radiosensitizers,w hereas the MOF scaffold acts as acontainer to encapsulate chemotherapeutic drug doxorubicin. In vitro and in vivo studies verify that the catalase-like nanohybrid significantly enhances the radiotherapye ffect, alleviating tumor hypoxia and achieving synergistic anticancer efficacy.T his hybrid nanomaterial remarkably suppresses the tumor growth with minimized systemic toxicity,o pening new horizons for the next generation of theranostic nanomedicines.

PLR and NLR measurements can provide important diagnostic and prognostic results in patients with resectable gastric cancer.

These experiments were designed to determine whether green tea extract (GTE), which contains polyphenolic free radical scavengers, prevents ischemia-reperfusion injury to the liver. Rats were fed a powdered diet containing 0-0.3% GTE starting 5 days before hepatic warm ischemia and reperfusion. Free radicals in bile were trapped with the spin-trapping reagent alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (4-POBN) and measured using electron spin resonance spectroscopy. Hepatic ischemia-reperfusion increased transaminase release and caused pathological changes including focal necrosis and hepatic leukocyte infiltration in the liver. Transaminase release was diminished by over 85% and pathological changes were almost totally blocked by 0.1% dietary GTE. Ischemia-reperfusion increased 4-POBN/radical adducts in bile nearly twofold, an effect largely blocked by GTE. Epicatechin, one of the major green tea polyphenols, gave similar protection as GTE. In addition, hepatic ischemia-reperfusion activated NF-kappa B and increased TNF-alpha mRNA and protein expression. These effects were all blocked by GTE. Taken together, these results demonstrate that GTE scavenges free radicals in the liver after ischemiareoxygenation, thus preventing formation of toxic cytokines. Therefore, GTE could prove to be effective in decreasing hepatic injury in disease states where ischemia-reperfusion occurs.

Background & Aims Foxp3+ T-regulatory cells (Tregs) maintain intestinal homeostasis under conditions of continuous challenge with inflammatory microbes. However, plasticity of the Treg population under certain conditions has been reported; Foxp3+ Tregs can be converted to Foxp3− CD4+ T cells. Methods We used mice with a T cell-induced colitis model to study the regulatory role of type I interferons (IFNs) in adaptive immunity. We transferred CD4+CD45RBhi (RBhi) T cells, with or without CD4+CD45RBlo CD25+ T cells, from wild-type or IFN-αβR−/− mice into Rag1−/− recipients. We analyzed induction of colitis by flow cytometry, confocal microscopy, and enzyme-linked immunosorbent assay and reverse-transcription polymerase chain reaction analyses. IFN-αβR−/−Rag−/− mice were given injections of recombinant IFN-a following transfer of IFN-αβR−/− RBhi T cells and CD4+Foxp3+ cells from Foxp3-eGFP mice. Results Signaling by type I IFNs was required for maintenance of Foxp3 expression and the suppressive activity of Tregs in mice. Transfer of CD4+CD45 RBloCD25+ Tregs from IFN-αβR−/− mice did not prevent T-cell induction of colitis in mice. Foxp3 expression by Tregs transferred from IFN-αβR−/− mice was significantly lower than that of Tregs from wild-type mice. Administration of recombinant IFN-α reduced T cell-mediated colitis by increasing the number of Foxp3+ Tregs and their suppressive functions. Conclusions Type I IFNs regulate intestinal homeostasis by maintaining Foxp3 expression on Tregs in colons of mice under inflammatory conditions.