Interleukin-6 (IL-6) is a multifunctional pro-inflammatory cytokine that is tightly regulated and expressed at low levels in healthy individuals. Increased IL-6 expression has been associated with a variety of diseases, including inflammatory conditions such as atherosclerosis and cardiovascular disease (obesity, myocardial infarction and type II diabetes). Cytokines including IL-6 and tumour necrosis factor alpha as well as acute phase proteins such as C-reactive protein (CRP) and fibrinogen are key biochemical risk factors for the development of these disease conditions. IL-6 is the key cytokine responsible for the stimulus of synthesis and secretion of CRP. IL-6 activates cell surface signalling via the assembly of IL-6, the IL-6 receptor (IL-6R) and the signalling receptor gp130. Assembly of the (hexameric) signalling complex of IL-6, IL-6R and gp130 occurs in a sequential manner and therefore this signalling complex lends itself to several potential sites for drug targeting. This review discusses some of the mechanisms of IL-6 signalling on various aspects of cardiovascular biology as well as some recent developments in drug targeting of this complex.

A range of epidemiological and experimental studies have indicated that suboptimal nutrition at different stages of gestation is associated with an increased prevalence of adult hypertension, cardiovascular disease, and obesity. The timing of prenatal nutrient restriction is important in determining postnatal outcomes-including obesity. The present study, aimed to determine the extent to which fetal adiposity and expression of the key thermogenic protein, uncoupling protein (UCP)1, are altered by restriction of maternal nutrient intake imposed during four different periods, starting from before conception. Maternal nutrient intake was restricted from 60 days before until 8 days after mating (periconceptional nutrient restriction; R-C), from 60 days before mating and throughout gestation (R-R), from 8 days gestation until term (C-R), or from 115 days gestation until term. Fetal perirenal adipose tissue (PAT) was sampled near to term at approximately 143 days. UCP1 mRNA, but not protein, abundance in PAT was increased in fetuses in the R-R group (C-C 63 +/- 18; R-C 83 +/- 43; C-R 103 +/- 38; R-R 167 +/- 50 arbitrary units (P < 0.05)). In contrast, the abundance of UCP1 mRNA, but not protein, in fetal PAT was decreased when maternal nutrition was restricted from 115 days gestation. The major effect of maternal nutrient restriction on adipose tissue deposition occurred in the C-R group, in which the proportion of fetal fat was doubled, whereas maternal nutrient restriction from 115 days gestation reduced fetal fat deposition. In conclusion, there are differential effects of maternal and therefore fetal nutrient restriction on UCP1 mRNA expression and fetal fat mass and these effects are dependent on the timing and duration of nutrient restriction.

We have characterized the localization and the ontogenetic changes in Neuropeptide tyrosine (NPY) before birth and investigated the regulation of NPY expression by cortisol and undernutrition in the fetal sheep hypothalamus during late gestation. Using immunohistochemistry, we have identified NPY-containing neurons in the infundibular nucleus and the internal layer of the median eminence in fetal hypothalami collected between 110 and 147 days gestation. NPY projections were also present in the paraventricular nucleus (PVN) of fetal hypothalami at all ages between 110 days gestation and term. There was a significant increase in the amount of immunoreactive NPY/g hypothalamus between 87 and 113 days and 131-140 days gestation and a further significant increase after 141 days gestation. The total hypothalamic content of immunoreactive NPY increased significantly between 87 and 113 days and 141-145 days gestation. The levels of NPY mRNA: 18S rRNA in the mediobasal region of the fetal hypothalamus were significantly higher at 145-146 days gestation than at any earlier gestational age between 116 and 141 days gestation. Cortisol (2.5-3.0 mg/24 h) was infused intrafetally between 109 and 116 days gestation. The ratio of NPY mRNA: 18s rRNA in the mediobasal region of the fetal hypothalamus was significantly higher in the cortisol-infused group when compared with the saline-infused control group at 116 days gestation. Maternal, and hence fetal undernutrition, was induced between 110 and 146 days gestation. At 145-146 days gestation the ratio of NPY mRNA: 18S rRNA in the mediobasal region of the fetal hypothalamus was significantly higher in the undernutrition group when compared with control animals. We have therefore demonstrated that NPY is present in the hypothalamus of the sheep fetus before birth and that hypothalamic NPY content and NPY mRNA increase before delivery. We have also found that glucocorticoids and undernutrition stimulate increases in NPY mRNA levels in the hypothalamus before birth.

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It is not clear if an increase in intra-adrenal cortisol is required to mediate the actions of adrenocorticotropic hormone (ACTH) on adrenal growth and steroidogenesis during the prepartum stimulation of the fetal pituitary-adrenal axis. We infused metyrapone, a competitive inhibitor of cortisol biosynthesis, into fetal sheep between 125 and 140 days of gestation (term = 147 +/- 3 days) and measured fetal plasma cortisol, 11-desoxycortisol, and ACTH; pituitary pro-opiomelanocortin mRNA and adrenal expression of ACTH receptor (melanocortin type 2 receptor), steroidogenic acute regulatory protein (StAR), 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), cytochrome P450 cholesterol side-chain cleavage (CYP11A1), cytochrome P450 17-hydroxylase (CYP17), 3beta-hydroxysteroid dehydrogenase, and cytochrome P450 21-hydroxylase mRNA; and StAR protein in the fetal adrenal gland. Plasma ACTH and 11-desoxycortisol concentrations were higher (P < 0.05), whereas plasma cortisol concentrations were not significantly different in metyrapone- compared with vehicle-infused fetuses. The ratio of plasma cortisol to ACTH concentrations was higher (P < 0.0001) between 136 and 140 days than between 120 and 135 days of gestation in both metyrapone- and vehicle-infused fetuses. The combined adrenal weight and adrenocortical thickness were greater (P < 0.001), and cell density was lower (P < 0.01), in the zona fasciculata of adrenals from the metyrapone-infused group. Adrenal StAR mRNA expression was lower (P < 0.05), whereas the levels of mature StAR protein (30 kDa) were higher (P < 0.05), in the metyrapone-infused fetuses. In addition, adrenal mRNA expression of 11betaHSD2, CYP11A1, and CYP17 were higher (P < 0.05) in the metyrapone-infused fetuses. Thus, metyrapone administration may represent a unique model that allows the investigation of dissociation of the relative actions of ACTH and cortisol on fetal adrenal steroidogenesis and growth during late gestation.