The immunosuppressive cytokine interleukin-4 increases the clonogenic potential of prostate stem-like cells by activation of STAT6 signalling

Interleukin-4 plays a critical role in the regulation of immune responses and has been detected at high levels in the tumour microenvironment of cancer patients, where concentrations correlate with the grade of malignancy. In prostate cancer, interleukin-4 has been associated with activation of the androgen receptor, increased proliferation and activation of survival pathways such as Akt and NF-κB. However, its role in therapy resistance has not yet been determined. Here we investigate the influence of interleukin-4 on primary epithelial cells from prostate cancer patients. Our data demonstrate an increase in the clonogenic potential of these cells when cultured in the presence of interleukin-4. In addition, a Phospho-Kinase Array revealed that in contrast to previously published work, signal transducer and activator of transcription6 (STAT6) is the only signalling molecule activated after interleukin-4 treatment. Using the STAT6-specific inhibitor AS1517499 we could confirm the role of STAT6 in increasing colony-forming frequency. However, clonogenic recovery assays revealed that interleukin-4 does not rescue the effects of either irradiation or docetaxel treatment. We therefore propose that although the interleukin-4/STAT6 axis does not appear to be involved in therapy resistance, it does play a crucial role in the colony-forming abilities of the basal cell population in prostate cancer. IL-4 may therefore contribute to disease relapse by providing a niche that is favourable for the clonogenic growth of prostate cancer stem cells

Effects of Inhibition of Interleukin-6 Signalling on Insulin Sensitivity and Lipoprotein (A) Levels in Human Subjects with Rheumatoid Diseases

Interleukin-6 (IL-6) is a pro-inflammatory cytokine that has been found to be increased in type 2 diabetic subjects. However, it still remains unclear if these elevated IL-6 levels are co-incidental or if this cytokine is causally related to the development of insulin resistance and type 2 diabetes in humans. Therefore, in the present study we examined insulin sensitivity, serum adipokine levels and lipid parameters in human subjects before and after treatment with the IL-6 receptor antibody Tocilizumab.11 non-diabetic patients with rheumatoid disease were included in the study. HOMA-IR was calculated and serum levels for leptin, adiponectin, triglycerides, LDL-cholesterol, HDL-cholesterol and lipoprotein (a) (Lp (a)) were measured before as well as one and three months after Tocilizumab treatment. The HOMA index for insulin resistance decreased significantly. While leptin concentrations were not altered by inhibition of IL-6 signalling, adiponectin concentrations significantly increased. Thus the leptin to adiponectin ratio, a novel marker for insulin resistance, exhibited a significant decrease. Serum triglycerides, LDL-cholesterol and HDL-cholesterol tended to be increased whereas Lp (a) levels significantly decreased.Inhibition of IL-6 signalling improves insulin sensitivity in humans with immunological disease suggesting that elevated IL-6 levels in type 2 diabetic subjects might be causally involved in the pathogenesis of insulin resistance. Furthermore, our data indicate that inhibition of IL-6 signalling decreases Lp (a) serum levels, which might reduce the cardiovascular risk of human subjects

In situ guided tissue regeneration in musculoskeletal diseases and aging: Implementing pathology into tailored tissue engineering strategies

In situ guided tissue regeneration, also addressed as in situ tissue engineering or endogenous regeneration, has a great potential for population-wide “minimal invasive” applications. During the last two decades, tissue engineering has been developed with remarkable in vitro and preclinical success but still the number of applications in clinical routine is extremely small. Moreover, the vision of population-wide applications of ex vivo tissue engineered constructs based on cells, growth and differentiation factors and scaffolds, must probably be deemed unrealistic for economic and regulation-related issues. Hence, the progress made in this respect will be mostly applicable to a fraction of post-traumatic or post-surgery situations such as big tissue defects due to tumor manifestation. Minimally invasive procedures would probably qualify for a broader application and ideally would only require off the shelf standardized products without cells. Such products should mimic the microenvironment of regenerating tissues and make use of the endogenous tissue regeneration capacities. Functionally, the chemotaxis of regenerative cells, their amplification as a transient amplifying pool and their concerted differentiation and remodeling should be addressed. This is especially important because the main target populations for such applications are the elderly and diseased. The quality of regenerative cells is impaired in such organisms and high levels of inhibitors also interfere with regeneration and healing. In metabolic bone diseases like osteoporosis, it is already known that antagonists for inhibitors such as activin and sclerostin enhance bone formation. Implementing such strategies into applications for in situ guided tissue regeneration should greatly enhance the efficacy of tailored procedures in the future

Inflammatory Response to a High Radiation Dose in Breast Cancer

Background: Radiation therapy (RT) is an essential treatment modality used for breast cancer (BC) care. Radiations can stimulate the immune system via the early activation of cytokine cascades, which can greatly affect cellular radio-sensitivity. Our aim is to analyze inflammatory response induced by high ionizing radiation (IR) doses, generated by intraoperative radiotherapy (IORT) treatment, to identify several potential targets that may influence cell radio-response. Methods: MCF10, MCF7 and MDA-MB231 BC cell lines have been exposed to high IR (23 Gray and 9 Gray), delivered by IORT treatments. Conditioned media (CM) were assayed at the time points: 0’, 30’, 1, 3, 6, 24, 48, and 72 hours, for production of cytokines, chemokines and growth factors by using Luminex technology. Results: We observed a very low cytokine concentration in MCF7 CM and a greater expression, of TH1 and TH2 cytokines, IL-7, G-CSF and MCP-1 in MCF10A CM. MDA-MB231 CM showed a reduced expression of TH1 and TH2 cytokines, IL-7, G-CSF, MCP-1 and an up-regulation of GM-CSF, IL-6 and IL-8 factors. Conclusions: Our results indicate that cytokine production in most cases is dose independent and time and cell type dependent. In particular, an over production at 24 hours after IORT treatment was observed. In addition, we speculate that MCF10A cells potentially exhibit an increased capacity to activate the immune system after IR exposure, and that MDAMB231 cells could have a role in radio-resistance phenotype through IL-6 and IL-8 high production activated by IR

Portrait of inflammatory response to ionizing radiation treatment

Ionizing radiation (IR) activates both pro-and anti-proliferative signal pathways producing an imbalance in cell fate decision. IR is able to regulate several genes and factors involved in cell-cycle progression, survival and/or cell death, DNA repair and inflammation modulating an intracellular radiation-dependent response. Radiation therapy can modulate anti-tumour immune responses, modifying tumour and its microenvironment. In this review, we report how IR could stimulate inflammatory factors to affect cell fate via multiple pathways, describing their roles on gene expression regulation, fibrosis and invasive processes. Understanding the complex relationship between IR, inflammation and immune responses in cancer, opens up new avenues for radiation research and therapy in order to optimize and personalize radiation therapy treatment for each patient

Identification of three particular morphological phenotypes in sporadic thoracic aortic aneurysm: Phenotype III as sporadic thoracic aortic aneurysm biomarker in aged individuals

Aging has a striking impact on the heart and the vascular system, and particularly on the large elastic arteries (i.e., aorta), resulting in a multitude of changes at different structural and functional levels. As result, medial degeneration (MD) occurs. A characteristic example of MD is sporadic thoracic aortic aneurysm (S-TAA), whose patho-physiological mechanisms remain unclear. In this study, typical MD morphological phenotypes were researched in S-TAA cases and control aorta specimens using histopathological and mainly immunohistochemical analyses. Three phenotypes (I, II, and III) were detected, but the phenotype III was observed. Elevated cystic MD, plurifocal medial apoptosis, and increased metalloproteinase-9 amount characterize it. In addition, it was significantly correlated with the severity of elastic fragmentation, hypertension, and smoking, and particularly with advancing age. Thus, phenotype III might represent the typical MD phenotype associated with S-TAA in old people that have a major risk of aorta rupture and dissection independently on aneurysm diameter. This might permit the assumption that phenotype III with its typical histological abnormalities is an optimal biomarker of rupture and/or dissection in aged individuals and is useful both for applying different surgical approaches and providing appropriate surgical indications