IL-17–producing Th17 cells mediate immune responses against a variety of fungal and bacterial infections. Signaling via NF-κB has been linked to the development and maintenance of Th17 cells. We analyzed the role of the unusual inhibitor of NF-κB, IκBNS, in the proliferation and effector cytokine production of murine Th17 cells. Our study demonstrates that nuclear IκBNS is crucial for murine Th17 cell generation. IκBNS is highly expressed in Th17 cells; in the absence of IκBNS, the frequencies of IL-17A–producing cells are drastically reduced. This was measured in vitro under Th17-polarizing conditions and confirmed in two colitis models. Mechanistically, murine IκBNS−/− Th17 cells were less proliferative and expressed markedly reduced levels of IL-2, IL-10, MIP-1α, and GM-CSF. Citrobacter rodentium was used as a Th17-inducing infection model, in which IκBNS−/− mice displayed an increased bacterial burden and diminished tissue damage. These results demonstrate the important function of Th17 cells in pathogen clearance, as well as in inflammation-associated pathology. We identified IκBNS to be crucial for the generation and function of murine Th17 cells upon inflammation and infection. Our findings may have implications for the therapy of autoimmune conditions, such as inflammatory bowel disease, and for the treatment of gut-tropic infections.
Abstract. Genipin, an active constituent of Gardenia fruit, has been reported to show an antitumor effect in several cancer cell systems. Here, we demonstrate how genipin exhibits a strong apoptotic cell death effect in human non-small-cell lung cancer H1299 cells. Genipin-mediated decrease in cell viability was observed through apoptosis as demonstrated by induction of a sub-G 1 peak through flow cytometry, DNA fragmentation measured by TUNEL assay, and cleavage of poly ADP-ribose-polymerase. During genipin-induced apoptosis, the mitochondrial execution pathway was activated by caspase-9 and -3 activation as examined by a kinetic study, cytochrome c release, and a dose-dependent increase in Bax/Bcl-2 ratio. A search for the downstream pathway reveals that genipin-induced apoptosis was mediated by an increase in phosphorylated p38MAPK expression, which further activated downstream signaling by phosphorylating ATF-2. SB203580, a p38MAPK inhibitor, markedly blocked the formation of TUNEL-positive apoptotic cells in genipin-treated cells. Besides, the interference of p38MAPK inhibited Bax expression and cytochrome c release. Altogether, our observations imply that genipin causes increased levels of Bax in response to p38MAPK signaling, which results in the initiation of mitochondrial death cascade, and therefore it holds promise as a potential chemotherapeutic agent for the treatment of H1299 cells.
MyD88-mediated signaling downstream of Toll-like receptors and the IL-1 receptor family is critically involved in the induction of protective host responses upon infections. Although it is known that MyD88-deficient mice are highly susceptible to a wide range of bacterial infections, the cell type-specific contribution of MyD88 in protecting the host against intestinal bacterial infection is only poorly understood. In order to investigate the importance of MyD88 in specific immune and nonimmune cell types during intestinal infection, we employed a novel murine knock-in model for MyD88 that enables the cell type-specific reactivation of functional MyD88 expression in otherwise MyD88-deficient mice. We report here that functional MyD88 signaling in CD11c+ cells was sufficient to activate intestinal dendritic cells (DC) and to induce the early group 3 innate lymphoid cell (ILC3) response as well as the development of colonic Th17/Th1 cells in response to infection with the intestinal pathogen C. rodentium. In contrast, restricting MyD88 signaling to several other cell types, including macrophages (MO), T cells or ILC3 did not induce efficient intestinal immune responses upon infection. However, we observed that the functional expression of MyD88 in intestinal epithelial cells (IEC) also partially protected the mice during intestinal infection, which was associated with enhanced epithelial barrier integrity and increased expression of the antimicrobial peptide RegIIIγ and the acute phase protein SAA1 by epithelial cells. Together, our data suggest that MyD88 signaling in DC and IEC is both essential and sufficient to induce a full spectrum of host responses upon intestinal infection with C. rodentium.
2556 Background: Epidemiology of NPC is characterized by a unique geographic distribution, with China having one of the highest incidence rates of NPC worldwide. Tislelizumab is an investigational monoclonal antibody with high affinity and specificity for PD-1. Tislelizumab was engineered to minimize binding to FcɤR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports from this phase 1/2 study (CTR20160872) have shown that single-agent tislelizumab was generally well tolerated and demonstrated preliminary antitumor activity in Chinese patients (pts) with advanced solid tumors. In the dose-verification part of this study, the recommended dose was established as 200 mg IV Q3W. Here we present preliminary results from the NPC cohort of this study. Methods: Chinese pts with advanced or metastatic, histologically or cytologically confirmed WHO type II-III NPC were enrolled in the indication-expansion phase of this study. Enrolled pts received tislelizumab 200 mg IV Q3W until unacceptable toxicity, consent withdrawal, or no evidence of continued clinical benefit. Antitumor activity (per RECIST v1.1) and safety/tolerability (per NCI-CTCAE v4.03) were assessed. Results: As of 11 May 2018, 20 NPC pts (median age 49 yr [range 35–61]) were enrolled. Most pts were male (85%) and non-smokers (65%). All pts received prior radiotherapy; 19 pts (95%) received ≥1 line of systemic treatment and the median number of prior lines of systemic treatment was 2 (range 0–10). At the cut-off date, 15 pts remain on treatment and the median study follow-up was 5.5 mo (range 0.46–9.0). Of 15 response-evaluable pts, 3 achieved a confirmed partial response (PR) and 9 achieved stable disease; 1 patient had an unconfirmed PR. Seven patients experienced ≥1 treatment-related AE (TRAE); hypothyroidism (n = 3) was the only TRAE that occurred in ≥2 pts. No grade ≥3 TRAEs or serious AEs were reported. Furthermore, no AEs led to either treatment interruption or discontinuation. Conclusions: Tislelizumab was generally well tolerated and demonstrated antitumor activity in previously treated pts with advanced NPC. Clinical trial information: CTR20160872.
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