A Protective Role by Interleukin-17F in Colon Tumorigenesis

Interleukin-17F (IL-17F), produced by Th17 cells and other immune cells, is a member of IL-17 cytokine family with highest homology to IL-17A. IL-17F has been shown to have multiple functions in inflammatory responses. While IL-17A plays important roles in cancer development, the function of IL-17F in tumorigenesis has not yet been elucidated. In the current study, we found that IL-17F is expressed in normal human colonic epithelial cells, but this expression is greatly decreased in colon cancer tissues. To examine the roles of IL-17F in colon cancer, we have used IL-17F over-expressing colon cancer cell lines and IL-17F-deficient mice. Our data showed decreased tumor growth of IL-17F-transfected HCT116 cells comparing to mock transfectants when transplanted in nude mice. Conversely, there were increased colonic tumor numbers and tumor areas in Il-17f−/− mice than those from wild-type controls after colon cancer induction. These results indicate that IL-17F plays an inhibitory role in colon tumorigenesis in vivo. In IL-17F over-expressing tumors, there was no significant change in leukocyte infiltration; instead, we found decreased VEGF levels and CD31+ cells. While the VEGF levels were increased in the colon tissues of Il-17f−/− mice with colon cancer. Together, our findings demonstrate a protective role for IL-17F in colon cancer development, possibly via inhibiting tumor angiogenesis

Investigation of the direct effects of salmon calcitonin on human osteoarthritic chondrocytes

<p>Abstract</p> <p>Background</p> <p>Calcitonin has been demonstrated to have chondroprotective effects under pre-clinical settings. It is debated whether this effect is mediated through subchondral-bone, directly on cartilage or both in combination. We investigated possible direct effects of salmon calcitonin on proteoglycans and collagen-type-II synthesis in osteoarthritic (OA) cartilage.</p> <p>Methods</p> <p>Human OA cartilage explants were cultured with salmon calcitonin [100 pM-100 nM]. Direct effects of calcitonin on articular cartilage were evaluated by 1) measurement of proteoglycan synthesis by incorporation of radioactive labeled ³⁵SO₄[5 μCi] 2) quantification of collagen-type-II formation by pro-peptides of collagen type II (PIINP) ELISA, 3) QPCR expression of the calcitonin receptor in OA chondrocytes using four individual primer pairs, 4) activation of the cAMP signaling pathway by EIA and, 5) investigations of metabolic activity by AlamarBlue.</p> <p>Results</p> <p>QPCR analysis and subsequent sequencing confirmed expression of the calcitonin receptor in human chondrocytes. All doses of salmon calcitonin significantly elevated cAMP levels (P < 0.01 and P < 0.001). Calcitonin significantly and concentration-dependently [100 pM-100 nM] induced proteoglycan synthesis measured by radioactive ³⁵SO₄incorporation, with a 96% maximal induction at 10 nM (P < 0.001) corresponding to an 80% induction of 100 ng/ml IGF, (P < 0.05). In alignment with calcitonin treatments [100 pM-100 nM] resulted in 35% (P < 0.01) increased PIINP levels.</p> <p>Conclusion</p> <p>Calcitonin treatment increased proteoglycan and collagen synthesis in human OA cartilage. In addition to its well-established effect on subchondral bone, calcitonin may prove beneficial to the management of joint diseases through direct effects on chondrocytes.</p

Homeostatic Regulation of Salmonella-Induced Mucosal Inflammation and Injury by IL-23

IL-12 and IL-23 regulate innate and adaptive immunity to microbial pathogens through influencing the expression of IFN-γ, IL-17, and IL-22. Herein we define the roles of IL-12 and IL-23 in regulating host resistance and intestinal inflammation during acute Salmonella infection. We find that IL-23 alone is dispensable for protection against systemic spread of bacteria, but synergizes with IL-12 for optimal protection. IL-12 promotes the production of IFN-γ by NK cells, which is required for resistance against Salmonella and also for induction of intestinal inflammation and epithelial injury. In contrast, IL-23 controls the severity of inflammation by inhibiting IL-12A expression, reducing IFN-γ and preventing excessive mucosal injury. Our studies demonstrate that IL-23 is a homeostatic regulator of IL-12-dependent, IFN-γ-mediated intestinal inflammation

Identification of the calcitonin receptor in osteoarthritic chondrocytes

<p>Abstract</p> <p>Background</p> <p>Preclinical and clinical studies have shown that salmon calcitonin has cartilage protective effects in joint degenerative diseases, such as osteoarthritis (OA). However, the presence of the calcitonin receptor (CTR) in articular cartilage chondrocytes is yet to be identified. In this study, we sought to further investigate the expression of the CTR in naïve human OA articular chondrocytes to gain further confirmation of the existents of the CTR in articular cartilage.</p> <p>Methods</p> <p>Total RNA was purified from primary chondrocytes from articular cartilage biopsies from four OA patients undergoing total knee replacement. High quality cDNA was produced using a dedicated reverse transcription polymerase chain reaction (RT-PCR) protocol. From this a nested PCR assay amplifying the full coding region of the CTR mRNA was completed. Western blotting and immunohistochemistry were used to characterize CTR protein on protein level in chondrocytes.</p> <p>Results</p> <p>The full coding transcript of the CTR isoform 2 was identified in all four individuals. DNA sequencing revealed a number of allelic variants of the gene including two potentially novel polymorphisms: a frame shift mutation, +473del, producing a shorter form of the receptor protein, and a single nucleotide polymorphism in the 3' non coding region of the transcript, +1443 C>T. A 53 kDa protein band, consistent with non-glycosylated CTR isoform 2, was detected in chondrocytes with a similar size to that expressed in osteoclasts. Moreover the CTR was identified in the plasma membrane and the chondrocyte lacuna of both primary chondrocytes and OA cartilage section.</p> <p>Conclusions</p> <p>Human OA articular cartilage chondrocytes do indeed express the CTR, which makes the articular a pharmacological target of salmon calcitonin. In addition, the results support previous findings suggesting that calcitonin has a direct anabolic effect on articular cartilage.</p

Interleukin-17 regulation: an attractive therapeutic approach for asthma

Interleukin (IL)-17 is recognized to play a critical role in numerous immune and inflammatory responses by regulating the expression of various inflammatory mediators, which include cytokines, chemokines, and adhesion molecules. There is growing evidence that IL-17 is involved in the pathogenesis of asthma. IL-17 orchestrates the neutrophilic influx into the airways and also enhances T-helper 2 (Th2) cell-mediated eosinophilic airway inflammation in asthma. Recent studies have demonstrated that not only inhibitor of IL-17 per se but also diverse regulators of IL-17 expression reduce antigen-induced airway inflammation, bronchial hyperresponsiveness, and Th2 cytokine levels in animal models of asthma. This review will summarize the role of IL-17 in the context of allergic airway inflammation and discuss the therapeutic potential of various strategies targeting IL-17 for asthma

A step towards scan time minimisation: simultaneous multislice-accelerated diffusion-weighted imaging of the liver

Purpose: To investigate the influence of different gradient preparation schemes and acceleration factors on acqusition time, image quality and quantitative parameters of simultaneous multislice-accelerated diffusion-weighted imaging of the liver in comparison to conventional sequences. Methods and Materials: Respiratory-triggered simultaneous multislice diffusion-weighted imaging (sms-DWI) of the liver was performed at 1.5 T in ten healthy volunteers using a monopolar (MP) versus a bipolar (BP) gradient preparation with an sms-acceleration factor (AF) of 2 and 3 and compared to conventional diffusion-weighted images (c-DWI). Qualitative image analysis was carried out by two independent readers. Signal-to-noise ratios (SNR) and apparent diffusion coefficient (ADC) values were measured in a region-of-interest analysis. Total scan time was measured. The Kruskal-Wallis test followed by Steel-Dwass comparisons was executed for statistical analysis with p-values < 0.05 considered significant. Results: Image quality in sms-DWI with AF2 was equivalenty high compared to c-DWI, with a reduction of scan time by 67%. AF3 resulted in only minor additional scan time reduction (by 69%) but was associated with a statistically significant deterioration of image quality. ADC values in sms-DWI were lower, SNR was higher as compared to c-DWI. Image quality was slightly higher using the MP diffusion preparation in sms-DWI and c-DWI. Conclusion: Sms-DWI with an AF of 2 is a promising approach for scan time minimization while maintaining high image quality in DWI of the liver. The diffusion preparation did not significantly influence image quality in sms-DWI. The lower ADC values in sms-DWI should be considered in diagnostic reading studies

Single-heartbeat cardiac cine imaging via jointly regularized non-rigid motion corrected reconstruction

PURPOSE: Develop a novel approach for 2D breath-hold cardiac cine from a single heartbeat, by combining cardiac motion corrected reconstructions and non-rigidly aligned patch-based regularization. METHODS: Conventional cardiac cine imaging is obtained via motion resolved reconstructions of data acquired over multiple heartbeats. Here, we achieve single-heartbeat cine imaging by incorporating non-rigid cardiac motion correction into the reconstruction of each cardiac phase, in conjunction with a motion-aligned patch-based regularization. The proposed Motion Corrected CINE (MC-CINE) incorporates all acquired data into the reconstruction of each (motion corrected) cardiac phase, resulting in a better posed problem than motion resolved approaches. MC-CINE was compared to iterative SENSE and XD-GRASP in fourteen healthy subjects in terms of image sharpness, reader scoring (1-5 range) and reader ranking (1-9 range) of image quality, and single-slice left ventricular assessment. RESULTS: MC-CINE was significantly superior to both iterative SENSE and XD-GRASP using 20, 2 and 1 heartbeat(s). Iterative SENSE, XD-GRASP and MC-CINE achieved sharpness of 74%, 74% and 82% using 20 heartbeats, and 53%, 66% and 82% with 1 heartbeat, respectively. Corresponding results for reader scores were 4.0, 4.7 and 4.9, with 20 heartbeats, and 1.1, 3.0 and 3.9 with 1 heartbeat. Corresponding results for reader rankings were 5.3, 7.3 and 8.6 with 20 heartbeats, and 1.0, 3.2 and 5.4 with 1 heartbeat. MC-CINE using a single heartbeat presented non-significant differences in image quality to iterative SENSE with 20 heartbeats. MC-CINE and XD-GRASP at one heartbeat both presented a non-significant negative bias of <2% in ejection fraction relative to the reference iterative SENSE. CONCLUSION: The proposed MC-CINE significantly improves image quality relative to iterative SENSE and XD-GRASP, enabling 2D cine from a single heartbeat

Simultaneous multislice accelerated diffusion-weighted imaging of the liver: comparison of different breathing schemes with standard sequences as reference

SMS-acceleration allows for considerable scan time reduction in hepatic DWI without substantial drawbacks in image quality both using respiratory-triggering and free-breathing acquisitions. In the present study set-up, ADC measured in SMS-DWI were lower than in standard DWI which should be considered when using absolute ADC for clinical reading. The demonstrated high image quality of SMS-DWI obtained in FB indicates great potential for scan time reduction in DWI for abdominal and whole-body applications

Measurement of Pulmonary Perfusion under Expiratory and Inspiratory Breathing Conditions using PCASL-bSSFP Imaging at 1.5 Tesla

Pseudo-continuous-arterial-spin-labeling (PCASL) has been successfully applied in the lung providing high quality perfusion images. The pulmonary blood flow and the respiratory system interact closely: the intrathoracic pressure has impact on the venous return. Therefore, in this work, we evaluate the effects of intrathoracic pressure on lung perfusion by using PCASL imaging in end-expiratory and end-inspiratory breath-hold. PCASL imaging is able to detect changes of parenchymal lung perfusion caused by alterations of the intrathoracic pressure. Perfusion signal measured under end-inspiratory condition were noticeably reduced as compared to end-expiratory breath-hold. This correlated significantly with measured blood flow volume through the pulmonary trunk