Overexpression of CIITA in T Cells Aggravates Th2-Mediated Colitis in Mice

The MHC class II transactivator (CIITA) is the master transcriptional regulator of genes involved in MHC class II restricted antigen presentation. Previously we suggested another role of CIITA in Th1/Th2 balance by demonstrating that forced expression of CIITA in murine T cells repressed Th1 immunity both in vitro and in vivo. However, the results were contradictory to the report that CIITA functioned to suppress the production of Th2 cytokine by CD4+ T cells in CIITA deficient mice. In this study, we investigated the influence of constitutive expression of CIITA in T cells on Th2 immune response in vivo using murine experimental colitis model. In the dextran sodium sulfate-induced acute colitis, a disease involving innate immunity, CIITA transgenic mice and wild type control mice showed similar progression of the disease. However, the development of oxazolone-induced colitis, a colitis mediated by predominantly Th2 immune response, was aggravated in CIITA-transgenic mice. And, CD4+ T cells from the mesenteric lymph node of CIITA-transgenic mice treated with oxazolone exhibited a high level of IL-4 secretion. Together, these data demonstrate that constitutive expression of CIITA in T cells skews immune response to Th2, resulting in aggravation of Th2-mediated colitis in vivo

Imidazole propionate ameliorates atopic dermatitis-like skin lesions by inhibiting mitochondrial ROS and mTORC2

BackgroundImidazole propionate (IMP) is a histidine metabolite produced by some gut microorganisms in the human colon. Increased levels of IMP are associated with intestinal inflammation and the development and progression of cardiovascular disease and diabetes. However, the anti-inflammatory activity of IMP has not been investigated. This study aimed to elucidate the role of IMP in treating atopic dermatitis (AD). MethodsTo understand how IMP mediates immunosuppression in AD, IMP was intraperitoneally injected into a Dermatophagoides farinae extract (DFE)/1-chloro-2,4 dinitrochlorobenzene (DNCB)-induced AD-like skin lesions mouse model. We also characterized the anti-inflammatory mechanism of IMP by inducing an AD response in keratinocytes through TNF-α/IFN-γ or IL-4 stimulation. ResultsContrary to the prevailing view that IMP is an unhealthy microbial metabolite, we found that IMP-treated AD-like skin lesions mice showed significant improvement in their clinical symptoms, including ear thickness, epidermal and dermal thickness, and IgE levels. Furthermore, IMP antagonized the expansion of myeloid (neutrophils, macrophages, eosinophils, and mast cells) and Th cells (Th1, Th2, and Th17) in mouse skin and prevented mitochondrial reactive oxygen species production by inhibiting mitochondrial energy production. Interestingly, we found that IMP inhibited AD by reducing glucose uptake in cells to suppress proinflammatory cytokines and chemokines in an AD-like in vitro model, sequentially downregulating the PI3K and mTORC2 signaling pathways centered on Akt, and upregulating DDIT4 and AMPK. DiscussionOur results suggest that IMP exerts anti-inflammatory effects through the metabolic reprogramming of skin inflammation, making it a promising therapeutic candidate for AD and related skin diseases

Cystamine induces AIF-mediated apoptosis through glutathione depletion

AbstractCystamine and its reduced form cysteamine showed protective effects in various models of neurodegenerative disease, including Huntington's disease and Parkinson's disease. Other lines of evidence demonstrated the cytotoxic effect of cysteamine on duodenal mucosa leading to ulcer development. However, the mechanism for cystamine cytotoxicity remains poorly understood. Here, we report a new pathway in which cystamine induces apoptosis by targeting apoptosis-inducing factor (AIF). By screening of various cell lines, we observed that cystamine and cysteamine induce cell death in a cell type-specific manner. Comparison between cystamine-sensitive and cystamine-resistant cell lines revealed that cystamine cytotoxicity is not associated with unfolded protein response, reactive oxygen species generation and transglutaminase or caspase activity; rather, it is associated with the ability of cystamine to trigger AIF nuclear translocation. In cystamine-sensitive cells, cystamine suppresses the levels of intracellular glutathione by inhibiting γ-glutamylcysteine synthetase expression that triggers AIF translocation. Conversely, glutathione supplementation completely prevents cystamine-induced AIF translocation and apoptosis. In rats, cysteamine administration induces glutathione depletion and AIF translocation leading to apoptosis of duodenal epithelium. These results indicate that AIF translocation through glutathione depletion is the molecular mechanism of cystamine toxicity, and provide important implications for cystamine in the neurodegenerative disease therapeutics as well as in the regulation of AIF-mediated cell death

Clinical significance of preoperative serum vascular endothelial growth factor, interleukin-6, and C-reactive protein level in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Angiogenesis is a multistep process in which many growth factors and cytokines have an essential role. Vascular endothelial growth factor (VEGF) is a potent angiogenic agent that acts as a specific mitogen for vascular endothelial cells through specific cell surface receptors. The interleukin-6 (IL-6) pathway is another mechanism linking angiogenesis to malignancy. C-reactive protein (CRP), a representative marker for inflammation, is known for its association with disease progression in many cancer types. The aim of this study was to determine preoperative serum levels of VEGF, IL-6, and CRP in colorectal carcinoma, and to correlate them with disease status and prognosis.</p> <p>Methods</p> <p>A 132 of 143 patients who underwent curative resection for colorectal cancer were enrolled in this study. 11 patients with resection margin positive were excluded. Factors considered in analysis of the relationship between VEGF, IL-6, and CRP and histological findings. Patient prognosis was investigated. Serum levels of VEGF and IL-6 were assessed using Enzyme-Linked Immuno-Sorbent Assay (ELISA), and CRP was measured using immunoturbidimetry.</p> <p>Results</p> <p>Median follow-up duration was 18.53 months (range 0.73-43.17 months) and median age of the patients was 62 years (range, 26-83 years). Mean and median levels of VEGF and CRP in colorectal cancer were significantly higher than in the normal control group; 608 vs. 334 pg/mL and 528 (range 122-3242) vs. 312 (range 16-1121) (<it>p </it>< 0.001); 1.05 mg/dL vs. 0.43 mg/dL and 0.22 (range 0.00-18.40) vs. 0.07 (range 0.02-6.94) (<it>p </it>= 0.002), respectively. However mean and median level of IL-6 in patients were not significantly higher than in control; 14.33 pg/mL vs. 5.65 pg/mL and 6.00 (range 1.02-139.17) vs. 5.30 (4.50-13.78) (<it>p </it>= 0.327). Although IL-6 and CRP levels were not correlated with other pathological findings, VEGF level was significantly correlated with tumor size (<it>p </it>= 0.012) and CEA (<it>p </it>= 0.038). When we established the cutoff value for VEGF (825 pg/mL), IL-6 (8.09 pg/mL), and CRP (0.51 mg/dL) by Receiver Operating Characteristic (ROC) curve, we noted that high VEGF levels tended to reduce overall survival (<it>p </it>= 0.053), but not significantly. However, IL-6 and CRP demonstrated no significance with regard to disease free survival (<it>p </it>= 0.531, <it>p </it>= 0.701, respectively) and overall survival (<it>p </it>= 0.563, <it>p </it>= 0.572, respectively). Multivariate analysis showed that VEGF (<it>p </it>= 0.032), CEA (<it>p </it>= 0.012), lymph node metastasis (<it>p </it>= 0.002), and TNM stage (<it>p </it>= 0.025) were independently associated with overall survival.</p> <p>Conclusions</p> <p>Preoperative serum VEGF and CRP level increased in colorectal cancer patients. High VEGF level has been proposed as a poor prognostic factor for overall survival in patients with colorectal cancer.</p

Timeliness of national notifiable diseases surveillance system in Korea: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>With the increase of international travels, infectious disease control is gaining a greater importance across regional borders. Adequate surveillance system function is crucial to prevent a global spread of infectious disease at the earliest stage. There have been limited reports on the characteristics of infectious disease surveillance in Asia. The authors studied the timeliness of the Korean National Notifiable Disease Surveillance System with regard to major notifiable diseases from 2001 to 2006.</p> <p>Methods</p> <p>Six notifiable infectious diseases reported relatively frequently were included in this study. Five diseases were selected by the criteria of reported cases > 100 per year: typhoid fever, shigellosis, mumps, scrub typhus, and hemorrhagic fever with renal syndrome. In addition, dengue fever was also included to represent an emerging disease, despite its low number of cases. The diseases were compared for the proportion notified within the recommended time limits, median time lags, and for the cumulative distribution of time lags at each surveillance step between symptom onset and date of notification to the Korea Centers for Disease Control and Prevention (KCDC).</p> <p>Results</p> <p>The proportion of cases reported in time was lower for disease groups with a recommended time limit of 1 day compared with 7 days (60%–70% vs. > 80%). The median time from disease onset to notification to KCDC ranged between 6 and 20 days. The median time from onset to registration at the local level ranged between 2 and 15 days. Distribution of time lags showed that main delays arose in the time from onset to diagnosis. There were variations in timeliness by disease categories and surveillance steps.</p> <p>Conclusion</p> <p>Time from disease onset to diagnosis generally contributed most to the delay in reporting. It is needed to promote public education and to improve clinical guidelines. Rapid reporting by doctors should be encouraged, and unification of recommended reporting time limit can be helpful. Our study also demonstrates the utility of the overall assessment of time-lag distributions for disease-specific strategies to improve surveillance.</p

Autoimmune Hemolytic Anemia in a Patient with Primary Ovarian Non-Hodgkin's Lymphoma

The primary ovarian lymphoma is a rare disease with poor prognosis. The incidence of autoimmune hemolytic anemia in patients with non-Hodgkin's lymphoma is estimated at 3%. However, a substantial portion of the previously reported cases of ovarian lymphoma actually represented ovarian involvement by more diffuse lymphomatous process. If stringent criteria are used for case selection, true primary ovarian lymphoma usually carries a favorable prognosis. We present a primary malignant lymphoma of ovary accompanied by autoimmune hemolytic anemia in a 29-yr-old patient. After ablative surgery, the hemoglobin level and the reticulocyte count were normalized. One year following surgery and chemotherapy, the patient is alive and disease free

Porcine sapovirus Cowden strain enters LLC-PK cells via clathrin- and cholesterol-dependent endocytosis with the requirement of dynamin II.

Caliciviruses in the genus Sapovirus are a significant cause of viral gastroenteritis in humans and animals. However, the mechanism of their entry into cells is not well characterized. Here, we determined the entry mechanism of porcine sapovirus (PSaV) strain Cowden into permissive LLC-PK cells. The inhibition of clathrin-mediated endocytosis using chlorpromazine, siRNAs, and a dominant negative (DN) mutant blocked entry and infection of PSaV Cowden strain, confirming a role for clathrin-mediated internalization. Entry and infection were also inhibited by the cholesterol-sequestering drug methyl-β-cyclodextrin and was restored by the addition of soluble cholesterol, indicating that cholesterol also contributes to entry and infection of this strain. Furthermore, the inhibition of dynamin GTPase activity by dynasore, siRNA depletion of dynamin II, or overexpression of a DN mutant of dynamin II reduced the entry and infection, suggesting that dynamin mediates the fission and detachment of clathrin- and cholesterol-pits for entry of this strain. In contrast, the inhibition of caveolae-mediated endocytosis using nystatin, siRNAs, or a DN mutant had no inhibitory effect on entry and infection of this strain. It was further determined that cell entry of PSaV Cowden strain required actin rearrangements for vesicle internalization, endosomal trafficking from early to late endosomes through microtubules, and late endosomal acidification for uncoating. We conclude that PSaV strain Cowden is internalized into LLC-PK cells by clathrin- and cholesterol-mediated endocytosis that requires dynamin II and actin rearrangement, and that the uncoating occurs in the acidified late endosomes after trafficking from the early endosomes through microtubules

An elevated likelihood of stroke, ischemic heart disease, or heart failure in individuals with gout: a longitudinal follow-up study utilizing the National Health Information database in Korea

ObjectiveAccumulating evidence from other countries indicates potential associations between gout and cardiovascular diseases; however, the associations of gout with cardiovascular diseases, particularly stroke, ischemic heart disease, and heart failure, remain ambiguous in the Korean population. We hypothesized that individuals with gout are at a higher likelihood of stroke, ischemic heart disease, or heart failure. This study expands upon previous research by ensuring a comparable baseline between patient and control groups and analyzing 16 years of data derived from an extensive healthcare database.MethodsWe selected 22,480 patients with gout and 22,480 control individuals from the Korean National Health Insurance Service-Health Screening Cohort database (2002–2019), and matched them at a 1:1 ratio according to sex, age, income, and residence. A Cox proportional hazard model with weighted overlap was employed to examine the relationship between gout and the risk of stroke, ischemic heart disease, or heart failure after adjustment for several covariates.ResultsThe incidences of stroke, ischemic heart disease, or heart failure in participants with gout were slightly higher than those in controls (stroke: 9.84 vs. 8.41 per 1000 person-years; ischemic heart disease: 9.77 vs. 7.15 per 1000 person-years; heart failure: 2.47 vs. 1.46 per 1000 person-years). After adjustment, the gout group had an 11% (95% confidence interval [CI] = 1.04–1.19), 28% (95% CI = 1.19–1.37), or 64% (95% CI = 1.41–1.91) higher likelihood of experiencing stroke, ischemic heart disease, or heart failure, respectively, than the control group.ConclusionThe present findings suggest that individuals with gout in the Korean population, particularly those aged ≥ 60 years, were more likely to have stroke, ischemic heart disease, or heart failure

In situ induction of dendritic cell–based T cell tolerance in humanized mice and nonhuman primates

Administration of an ICAM-1–specific antibody arrests dendritic cells in a semi-immature state and facilitates antigen-specific T cell tolerance to islet allografts in humanized mice and Rhesus monkeys