Updated recommendations of the International Dengue Initiative expert group for CYD-TDV vaccine implementation in Latin America.

Dengue disease represents a large and growing global threat to public health, causing a significant burden to health systems of endemic countries. For countries considering vaccination as part of their Integrated Management Strategy for Prevention and Control of Dengue, the World Health Organization currently recommends the first licensed dengue vaccine, CYD-TDV for: individuals aged 9 years or above from populations with high transmission rates, based on either seroprevalence criteria or pre-vaccination screening strategies, and for persons with confirmed prior exposure to infection in moderate to lower transmission settings. This paper describes the main conclusions of the Sixth Meeting of the International Dengue Initiative (IDI) held in June 2018, following release of a new product label by the manufacturer, updated WHO-SAGE recommendations, additional scientific evidence on vaccine performance, and reports of experiences by implementing countries. Considerations were made regarding the need for improving the quality of epidemiological and surveillance data in the region to help define the convenience of either of the two vaccination strategies recommended by WHO-SAGE. Extensive discussion was dedicated to the pros and cons of implementing either of such strategies in Latin America. Although, in general, a seroprevalence-based approach was preferred in high transmission settings, when cost-effectivity is favorable pre-vaccination screening is a convenient alternative. Cost-effectiveness evaluations can assist with the decisions by public health authorities of whether to introduce a vaccine. Where implemented, vaccine introduction should be part of a public health strategy that includes the participation of multiple sectors of society, incorporating input from scientific societies, ministries of heath, and civil society, while ensuring a robust communication program.

IL-6 promoter is modulated by the 24 kDa FGF-2 isoform fused to the hormone binding domain of the oestrogen receptor.

Fusion proteins consisting of the 24 kDa nuclear form of basic fibroblast growth factor (FGF-2), associated with the hormone binding domain of oestrogen receptor (HBD), convey oestrogen inducibility to FGF-2. When stable HBD-FGF-2 HeLa cell lines were transiently transfected with an interleukin 6 (IL-6) construct, the IL-6 promoter activity was downregulated by the addition of oestradiol. Moreover, in these cell lines, the function of the FGF-2 nuclear localisation sequence was abolished by its fusion to HBD, while addition of oestradiol restored the location of the chimera to the nucleus.

The high molecular weight isoforms of basic fibroblast growth factor (FGF-2): an insight into an intracrine mechanism.

Basic fibroblast growth factor (FGF-2) is an important modulator of cell growth and differentiation under both physiological and pathological conditions. Until recently, most investigations into the FGF-2 signalling pathway were concerned with its interaction with specific membrane receptors. Nevertheless, while a 18 kDa protein of FGF-2 is cytosolic, there are also co-translated high molecular weight (HMW) isoforms that are predominantly located in the cell nucleus. An increasing amount of data strongly argue in favour of distinct biological functions depending on the subcellular location of the FGF-2 species. This review describes the evidence concerning the strictly intracellular mode of action of the HMW isoforms of FGF-2.

Expression of the interleukin-6 gene is constitutive and not regulated by estrogen in rat vascular smooth muscle cells in culture.

Vascular smooth muscle cells (SMC) are major constituents of the medial layer of blood vessels and are involved in the development of atherosclerotic plaque. SMC secrete copious IL-6 under basal conditions that can be increased by cytokines such as tumor necrosis factor-alpha and interleukin-1beta (IL-1beta). The goal of our studies was to define the role of estrogen in IL-6 production by SMC. In a first series of experiments, the expression of specific messenger RNAs as well as the production of IL-6 bioactivity by rat SMC in culture could be demonstrated in basal and IL-1-stimulated conditions, but was unaffected by estrogen treatment. Different constructs containing deleted or mutated fragments of the human IL-6 promoter driving luciferase or chloramphenicol acetyltransferase reporter gene were then transiently transfected in these cells. A significant basal activity that was increased 2- to 4-fold after IL-1beta stimulation was observed with the total IL-6 promoter. Deletion analysis indicated that the -158/+11 region containing activator protein-1 and cAMP response element sites was apparently the minimal region of IL-6 promoter to confer both constitutive and IL-1-inducible activities. Site-directed mutagenesis experiments suggest that basal activity is dependent upon the promoter sequence -158 to -112 containing the nuclear factor (NF)-IL6(-153) and Sp1 sites, whereas IL-1beta stimulation would depend on the residual -112 nucleotides containing NF-IL6(-75) and NF-kappaB sites. In contrast to the down-regulation of IL-6 expression by estrogen described in osteoblasts, ethinyl estradiol as well as 17beta-estradiol did not influence stimulated IL-6 activity in our experimental conditions whatever the construct tested, even when either estrogen receptor alpha or beta was overexpressed. Thus, the atheroprotective properties of estrogen are probably not mediated through the regulation of IL-6 production by SMC.

Inhibition of interleukin-6 promoter activity by the 24 kDa isoform of fibroblast growth factor-2 in HeLa cells.

The expression of the interleukin (IL-6) gene can be regulated by various activating or inhibitory stimuli. This modulation involves several regulatory binding sites on the IL-6 promoter, and appears to be in general cell-specific. We have previously described that the nuclear 24 kDa isoform of fibroblast growth factor-2 (FGF-2) is able to increase IL-6 gene expression in NIH-3T3 cells. The transduction pathway involved was shown to be distinct from the extracellular mode of action of the smallest 18 kDa FGF-2 isoform. In the present study, we show that 24 kDa FGF-2-encoding vectors transfected into HeLa cells inhibit various co-transfected constructs incorporating the promoter element of the IL-6 gene and either the luciferase or the chloramphenicol acetyltransferase units. This down-regulation occurs dose-dependently with the 24 kDa FGF-2, is IL-6-promoter-specific, and does not involve an autocrine loop of the growth factor, since exogenously added FGF-2 fails to modulate the IL-6 promoter activity. Furthermore, 24 kDa FGF-2 inhibits the activity of both the co-transfected deletion mutants IL-6(-224) and IL-6(-158), and the point-mutated IL-6 promoter constructs in which the activating protein-1, nuclear factor (NF)-IL-6 and NF-kappaB elements are disrupted. We identify a responsive region to 24 kDa FGF-2 between positions -158 and -109 on the IL-6 promoter, which notably contains a retinoblastoma control element.

Overexpression of the FGF-2 24-kDa isoform up-regulates IL-6 transcription in NIH-3T3 cells.

We have isolated NIH-3T3 cell lines overexpressing the nuclear 24-kDa isoform of fibroblast growth factor (FGF)-2 and characterized its regulatory effect on the expression of interleukin-6 (IL-6) in these cells. The clone pRF5 expressing the highest level was able to grow in 1% serum medium to a high saturation density and acquired a radioresistance advantage. In pRF5 and another clone pRF1, IL-6 RNA levels were markedly increased. Studies with IL-6 promoter constructs revealed that IL-6 gene up-regulation occurred at the transcriptional level and did not involve the AP-1 binding site. Exogenously added 18-kDa isoform of FGF-2 (100 ng/ml) produced down-regulation of IL-6 involving an AP-1 binding site, thus suggesting a receptor-independent pathway for the intracellular 24-kDa isoform.