RANKL Enhances Macrophage Paracrine Pro-Calcific Activity in High Phosphate-Treated Smooth Muscle Cells: Dependence on IL-6 and TNF-α

Background: Vascular calcification is highly correlated with cardiovascular disease (CVD) morbidity and mortality, and it is associated with inflammation. Receptor activator of NF-?B ligand (RANKL) inhibition in vivo has been shown to reduce vascular calcification in a mouse model of atherosclerosis. Therefore, we tested the hypothesis that RANKL regulates smooth muscle cell (SMC) calcification by modulating macrophage production of pro-calcific cytokines. Methods: We used a bone marrow-derived macrophage (BMDM)/SMC co-culture system and examined the effects of RANKL on BMDM activation and SMC matrix calcification. Results: Treatment with RANKL alone did not stimulate SMC calcification induced by elevated phosphate. BMDMs differentiated with macrophage colony-stimulating factor and placed in co-culture with SMCs increased phosphate-induced SMC calcification. RANKL added to the BMDM/SMC co-cultures further enhanced SMC calcification. Treatment of BMDMs with RANKL resulted in increased expression of IL-6 and TNF-α. Thus, increased expression of these pro-calcific cytokines in macrophages may mediate RANKL-induced SMC calcification in a paracrine fashion. Addition of neutralizing IL-6 and TNF-α antibodies together with RANKL treatment significantly reduced the RANKL induction of SMC calcification. Conclusion: RANKL activation of pro-inflammatory and pro-calcific pathways in macrophages may contribute to vascular calcification and inflammation.     

What Do Cytokine Profiles Tell Us About Subsets of Juvenile Idiopathic Arthritis?

Classification of juvenile idiopathic arthritis is an ongoing process and up to now has been predominantly based on clinical manifestations—mainly number of joints at onset of disease. In the meantime, basic studies have advanced our knowledge regarding the disease pathogenesis. Unfortunately, studies of cytokines and cytokine polymorphisms have not followed the predominantly clinical International League of Associations for Rheumatology classification in that no significant biological differences among the different disease categories have been demonstrated with robust associations. Only systemic-onset disease seems to be quite different from other disease categories with regard to biologic mechanisms; indeed, it now seems closer to autoinflammatory than to classic autoimmune diseases. New players in the immunologic basis of juvenile idiopathic arthritis (eg, interleukin-17 and regulatory T cells) are also discussed in this review.     

Vitamin D3 modulates T lymphocyte responses in hepatitis C virus-infected liver transplant recipients

Background

Aim of the present study was to investigate whether 1,25(OH)(2)D(3) (Vitamin D3) modulates T lymphocyte functions in patients transplanted for hepatitis C virus-related cirrhosis.

Methods

Sixteen patients and ten healthy subjects were investigated. T lymphocytes were activated in vitro in the presence or absence of Vitamin D3 and then the proliferative response and IFN-γ and TNF-α production were assessed.

Results

Vitamin D3 potently reduced T-lymphocyte proliferation in a dose-related fashion. Similarly, FACS analysis and ELISA testing demonstrated that Vitamin D3 significantly decreased the response frequency and the response intensity of IFN-γ and TNF-α production in the whole CD3-positive T lymphocyte population as well as in “naive” CD4+ CD45RA+ and “memory” CD4+ CD45RO+ T lymphocyte subsets. The inhibitory effect of Vitamin D3 on T-cell proliferation and cytokine production was not different between patients and controls. No toxic effects were exerted by Vitamin D3 even at the higher concentration used (10 nM). Finally, no statistically significant correlation was found between 25(OH)D serum levels and the proliferative response or cytokine production of T lymphocytes from transplanted patients.

Conclusions

This study demonstrates that in patients transplanted for hepatitis C virus-related cirrhosis Vitamin D3 modulates T lymphocyte activation, and provides a rationale for the evaluation of this compound as an immunosuppressive agent in liver-transplanted patients.     

The role of cytoreductive surgery in advanced-stage ovarian cancer: a systematic review

It has already been proven that ovarian cancer is the sixth most common cancer among women, and it is considered the leading cause of death by gynecologic cancer in developed countries. This article is a literature review based on the use of cytoreductive surgery matched with adjuvant chemotherapy in advanced-stage ovarian cancer. According to the statistics, the difficulty of obtaining an early diagnosis results in a delay in the disease treatment and as a consequence, in many cases, ovarian cancer is still diagnosed in the advanced stage of the disease. Primary surgery is performed, in addition to diagnosis and staging, to achieve optimal cytoreduction. The purpose of this article is to review the different surgical approaches in the management of epithelial ovarian cancer, specifically the high-stage disease, with a special concentration on the most recent therapeutic additions to our current knowledge, such as hyperthermic intraperitoneal chemotherapy and new therapeutic drugs. Surgical treatment still plays a pivotal role in the management of advanced-stage ovarian cancer. Complete cytoreduction continues to be, when feasible, the objective to be attempted in the surgical treatment of advanced ovarian cancer. Obviously, the success of the operation depends on numerous factors, including patient selection, the locations of tumors, and surgeon expertise. To offer patients the best possible outcome with the least accompanying morbidity, strong consideration should be given to the referral of such patients to expert care centers for primary surgery, because it may be the best means currently available for improving overall survival.