17-beta estradiol and progesterone-induced alterations in human type-1/type-2 cytokine balance and the role of costimulatory and apoptotic mechanisms

Evidence suggests that sex-based differences in immune function may predispose women to numerous hypersensitivity conditions such as Systemic lupus erythematosus (SLE), Hashimoto's thyroiditis and asthma. To date, the exact mechanisms of sexual dimorphism in immunity are not fully characterized but sex hormones such as 17-β estradiol (E2) and progesterone (PR) are believed to be involved. Since E2 and PR may modulate the production of critical regulatory cytokines, we sought to characterize their effects on the in vitro human type-1/type-2 cytokine balance. We hypothesized that E2 and/or PR vary cytokine production and influence costimulatory molecule expression and apoptosis. We first described the effect of E2 and/or PR on type-1 (IFN-γ and IL-12) and type-2 (IL-4 and IL-10) cytokine production by human peripheral blood mononuclear cells (PBMC) treated with various T-lymphocyte and monocyte stimuli. E2 and/or PR were each used at concentrations similar to those found at the maternal-fetal interface during pregnancy. At this dose, E2 increased IFN-γ and IL-12 production and PR decreased IFN-γ production and tended to increase IL-4 production. Furthermore, the combination of E2+PR decreased IL-12 production. This suggests that E2 shifts the type-1/type-2 cytokine balance towards a type-1 response and that PR and E2+PR shift the balance towards a type-2 response. Next, we used intracellular cytokine detection to demonstrate that E2 and/or PR are capable of altering cytokine production of CD3+ T-cells and the CD3+CD4+ and CD3+CD8+ subsets. In addition, we used the H9 T-lymphocyte cell line and the THP-1 monocyte cell line to show that E2 and/or PR can induce cytokine effects in both T-cells and monocytes independent of their interaction. Lastly, we determined the effect of E2 and/or PR on costimulatory molecule expression and apoptosis as potential mechanisms for the cytokine-induced alterations. E2 increased and PR decreased CD80 expression on THP-1 cells and PR and E2+PR decreased CD28 expression in PBMC and Jurkat cells. Furthermore, E2, PR and E2+PR increased Fas-mediated apoptosis in Jurkat cells and E2 increased FasL expression on THP-1 cells. Thus, E2 and/or PR may alter the cytokine balance by modulating the CD28/CD80 costimulatory pathway and apoptosis. ^

Delta like ligand 4 is a critical regulator of bone marrow cell differentiation into pericytes/vascular smooth muscle cells and is essential for the vasculogenesis that supports the growth of Ewing’s sarcoma

We have previously shown that vasculogenesis, the process by which bone marrow-derived cells are recruited to the tumor and organized to form a blood vessel network de novo, is essential for the growth of Ewing’s sarcoma. We further demonstrated that these bone marrow cells differentiate into pericytes/vascular smooth muscle cells(vSMC) and contribute to the formation of the functional vascular network. The molecular mechanisms that control bone marrow cell differentiation into pericytes/vSMC in Ewing’s sarcoma are poorly understood. Here, we demonstrate that the Notch ligand Delta like ligand 4 (DLL4) plays a critical role in this process. DLL4 is essential for the formation of mature blood vessels during development and in several tumor models. Inhibition of DLL4 causes increased vascular sprouting, decreased pericyte coverage, and decreased vessel functionality. We demonstrate for the first time that DLL4 is expressed by bone marrow-derived pericytes/vascular smooth muscle cells in two Ewing’s sarcoma xenograft models and by perivascular cells in 12 out of 14 patient samples. Using dominant negative mastermind to inhibit Notch, we demonstrate that Notch signaling is essential for bone marrow cell participation in vasculogenesis. Further, inhibition of DLL4 using either shRNA or the monoclonal DLL4 neutralizing antibody YW152F led to dramatic changes in blood vessel morphology and function. Vessels in tumors where DLL4 was inhibited were smaller, lacked lumens, had significantly reduced numbers of bone marrow-derived pericyte/vascular smooth muscle cells, and were less functional. Importantly, growth of TC71 and A4573 tumors was significantly inhibited by treatment with YW152F. Additionally, we provide in vitro evidence that DLL4-Notch signaling is involved in bone marrow-derived pericyte/vascular smooth muscle cell formation outside of the Ewing’s sarcoma environment. Pericyte/vascular smooth muscle cell marker expression by whole bone marrow cells cultured with mouse embryonic stromal cells was reduced when DLL4 was inhibited by YW152F. For the first time, our findings demonstrate a role for DLL4 in bone marrow-derived pericyte/vascular smooth muscle differentiation as well as a critical role for DLL4 in Ewing’s sarcoma tumor growth.

The effects of obesity in critical illness

Obesity continues to cripple the United States in terms of increasing health care expenditures and its rising rate of prevalence in epidemic proportions. The comorbidities associated with obesity have continued to represent some of the most deadly chronic health diseases. The most vulnerable subpopulation, the critically ill, suffers from not only the comorbid conditions but also the complications encountered within their specialized care. Taking into account the rising prevalence rates of obesity and critical care patients, it has come to the attention of many researchers to measure the trends associated with these two health conditions. Hospital mortality was found to be lower in higher BMI groups whereas there was no difference between BMI groups for ICU mortality. Length of stay and mechanical ventilation were both higher for obese rather than non-obese patients. The most prevalent disease states among the obese critically injured was cardiovascular and pulmonary disease. In conclusion, obesity is not independently associated with increased ICU mortality, but the comorbidities linked to obesity prove a greater threat to vitality.^

A critical review: Why isn't "cold pasteurization" being used widespread as a method to prevent food-related illnesses as a result of the consumption of ready-to-eat, fresh fruits, and vegetables

The Centers for Disease Control estimates that foodborne diseases cause approximately 76 million illnesses, 325,000 hospitalizations, and 5,000 deaths in the United States each year. The American public is becoming more health conscious and there has been an increase in the dietary intake of fresh fruits and vegetables. Affluence and demand for convenience has allowed consumers to opt for pre-processed packaged fresh fruits and vegetables. These pre-processed foods are considered Ready-to-Eat. They have many of the advantages of fresh produce without the inconvenience of processing at home. After seeing a decline in food-related illnesses between 1996 and 2004, due to an improvement in meat and poultry safety, tainted produce has tilted the numbers back. This has resulted in none of the Healthy People 2010 targets for food-related illness reduction being reached. Irradiation has been shown to be effective in eliminating many of the foodborne pathogens. The application of irradiation as a food safety treatment has been widely endorsed by many of the major associations involved with food safety and public health. Despite these endorsements there has been very little use of this technology to date for reducing the disease burden associated with the consumption of these products. A review of the available literature since the passage of the 1996 Food Quality Protection Act was conducted on the barriers to implementing irradiation as a food safety process for fresh fruits and vegetables. The impediments to adopting widespread utilization of irradiation food processing as a food safety measure involve a complex array of legislative, regulatory, industry, and consumer issues. The FDA’s approval process limits the expansion of the list of foods approved for the application of irradiation as a food safety process. There is also a lack of capacity within the industry to meet the needs of a geographically dispersed industry.^