The prolactin receptor is expressed in rheumatoid arthritis and psoriatic arthritis synovial tissue and contributes to macrophage activation.

OBJECTIVES: Prolactin (PRL) is a lactation-inducing hormone with immunomodulatory properties and is found at elevated levels in the serum of patients with RA and other rheumatic diseases. The PRL receptor (PRLR) has been shown to be expressed by macrophages in atherosclerotic plaques. The aim of this study was to examine PRLR expression by synovial macrophages and its role in the regulation of macrophage activation. METHODS: Serum monomeric 23 kDa PRL levels were measured in 119 RA patients using a fluoroimmunometric assay. PRLR expression was assessed in synovial tissue of 91 RA, 15 PsA and 8 OA patients by immunohistochemistry and digital image analysis. Double IF was used to identify PRLR-expressing cells. The effects of PRL on monocyte-derived macrophage gene expression were examined by quantitative real-time PCR and ELISA. RESULTS: Serum PRL levels were similar in female and male RA patients. Median (interquartile range) PRLR expression was significantly higher (P < 0.05) in RA and PsA synovial tissue compared with OA. PRLR colocalized with synovial CD68+ macrophages and von Willebrand factor+ endothelial cells. In vitro, PRLR was prominently expressed in IFN-γ-and IL-10-polarized macrophages compared with other polarizing conditions. PRL by itself had negligible effects on macrophage gene expression, but cooperated with CD40L and TNF to increase expression of pro-inflammatory genes including IL-6, IL-8 and IL-12ß. CONCLUSIONS: Synovial PRLR expression is enhanced in patients with inflammatory arthritis compared with OA, and PRL cooperates with other pro-inflammatory stimuli to activate macrophages. These results identify PRL and PRLR as potential new therapeutic targets in inflammatory arthritis.

Infusion of a lipid emulsion in healthy men decreases the serotonergic response.

Subjects with obesity and insulin resistance display a low response to a serotonergic challenge test. One of the hallmarks of obesity and insulin resistance is elevated plasma free fatty acids (FFAs). We hypothesize that increasing plasma FFA by infusion of a lipid emulsion, may be a contributing component leading to decreased serotonergic responsivity in healthy young men. Ten lean healthy men, 23.6 ± 5.0 years and BMI 22.6 ± 1.9 kg/m(2), were included. Serotonergic responsivity was assessed using the prolactin response to infusion with citalopram, a selective serotonin reuptake inhibitor, which is a validated tool to assess serotonergic tone. All participants received a lipid/heparin emulsion (Intralipid) infusion during 6 h. Saline infusion was used as a control. To evaluate a possible effect of heparin per se on prolactin, four out of the ten subjects also received heparin only during 6 h without the serotonergic challenge test. Plasma prolactin increased by 74.3 ± 15.5% during saline infusion. Intralipid infusion increased plasma FFA from 0.5 ± 0.05 to 2.3 ± 0.2 mmol/l (p < 0.001). The increase in plasma prolactin during Intralipid infusion was significantly lower (39.3 ± 10%; p < 0.001 compared to saline infusion). Heparin infusion per se increased plasma prolactin by 14.0 ± 1.9%. We found that during the Intralipid infusion with concomitant high plasma FFA levels the serotonergic response was decreased in healthy young men. Higher FFA levels may be the mediator of the decreased serotonergic response reported in patients with insulin resistance and obesity.

Prolactin and venous thrombosis: indications for a novel risk factor?

OBJECTIVE: Several acquired risk factors for venous thrombosis (VT) are associated with high prolactin levels. Our goal was to investigate VT risk for different levels of prolactin. METHODS AND RESULTS: We used data of a case-control study on leg vein thrombosis conducted between September 1999 and August 2006 at the Academic Medical Center, Amsterdam, the Netherlands. Prolactin was assessed in 187 cases (mean age, 57 years; range, 19 to 90) and 374 gender-matched controls (mean age, 57 years; range, 18 to 93). Odds ratios and 95% CI for VT risk were estimated based on several cutoff levels derived from prolactin levels in controls. Odds ratios for VT risk clearly increased with higher prolactin levels. For prolactin levels above the 75th percentile (8 µg/L), we found an odds ratio of 1.7 (95% CI 1.0 to 2.7) as compared with levels below the 50th percentile (6 µg/L). This further increased up to an odds ratio of 4.7 (95% CI 1.8 to 11.8) for prolactin levels above the 97.5th percentile (16 µg/L). The risk was most pronounced in premenopausal women. CONCLUSIONS: Our data suggest that prolactin levels are associated with VT in a dose-dependent fashion. Future studies are needed to evaluate the causality of this relationship.

Cardiac Autonomic Nervous System Activation and Metabolic Profile in Young Children: The ABCD Study.

BACKGROUND: In adults, increased sympathetic and decreased parasympathetic nervous system activity are associated with a less favorable metabolic profile. Whether this is already determined at early age is unknown. Therefore, we aimed to assess the association between autonomic nervous system activation and metabolic profile and its components in children at age of 5-6 years. METHODS: Cross-sectional data from an apparently healthy population (within the ABCD study) were collected at age 5-6 years in 1540 children. Heart rate (HR), respiratory sinus arrhythmia (RSA; parasympathetic activity) and pre-ejection period (PEP; sympathetic activity) were assessed during rest. Metabolic components were waist-height ratio (WHtR), systolic blood pressure (SBP), fasting triglycerides, glucose and HDL-cholesterol. Individual components, as well as a cumulative metabolic score, were analyzed. RESULTS: In analysis adjusted for child's physical activity, sleep, anxiety score and other potential confounders, increased HR and decreased RSA were associated with higher WHtR (P< 0.01), higher SBP (p<0.001) and a higher cumulative metabolic score (HR: p < 0.001; RSA: p < 0.01). Lower PEP was only associated with higher SBP (p <0.05). Of all children, 5.6% had 3 or more (out of 5) adverse metabolic components; only higher HR was associated with this risk (per 10 bpm increase: OR = 1.56; p < 0.001). CONCLUSIONS: This study shows that decreased parasympathetic activity is associated with central adiposity and higher SBP, indicative of increased metabolic risk, already at age 5-6 years.

Prolactin receptor antagonism uncouples lipids from atherosclerosis susceptibility.

The pituitary-derived hormone prolactin has been suggested to stimulate the development of atherosclerosis and cardiovascular disease through its effects on metabolism and inflammation. In this study, we aimed to challenge the hypothesis that inhibition of prolactin function may beneficially affect atherosclerosis burden. Hereto, atherosclerosis-susceptible LDL receptor (Ldlr) knockout mice were transplanted with bone marrow from transgenic mice expressing the pure prolactin receptor antagonist Del1-9-G129R-hPRL or their non-transgenic littermates as control. Recipient mice expressing Del1-9-G129R-hPRL exhibited a decrease in plasma cholesterol levels (-29%; P<0.05) upon feeding a Western-type diet (WTD), which could be attributed to a marked decrease (-47%; P<0.01) in the amount of cholesterol esters associated with pro-atherogenic lipoproteins VLDL/LDL. By contrast, Del1-9-G129R-hPRL-expressing mice did not display any change in the susceptibility for atherosclerosis after 12 weeks of WTD feeding. Both the absolute atherosclerotic lesion size (223 ± 33 × 10(3) µm(2) for Del1-9-G129R-hPRL vs 259 ± 32 × 10(3) µm(2) for controls) and the lesional macrophage and collagen contents were not different between the two groups of bone marrow recipients. Importantly, Del1-9-G129R-hPRL exposure increased levels of circulating neutrophils (+91%; P<0.05), lymphocytes (+55%; P<0.05), and monocytes (+43%; P<0.05), resulting in a 49% higher (P<0.01) total blood leukocyte count. In conclusion, we have shown that prolactin receptor signaling inhibition uncouples the plasma atherogenic index from atherosclerosis susceptibility in Ldlr knockout mice. Despite an associated decrease in VLDL/LDL cholesterol levels, application of the prolactin receptor antagonist Del1-9-G129R-hPRL does not alter the susceptibility for initial development of atherosclerotic lesions probably due to the parallel increase in circulating leukocyte concentrations.

Maternal prepregancy BMI and lipid profile during early pregnancy are independently associated with offspring's body composition at age 5-6 years: the ABCD study.

BACKGROUND: There is growing evidence that disturbances in maternal metabolism and, subsequently, intrauterine conditions affect foetal metabolism. Whether this has metabolic consequences in offspring later in life is not fully elucidated. We investigated whether maternal pre-pregnancy body mass index (pBMI) is associated with offspring's adiposity at age 5-6 years and whether this association is mediated by the mother's lipid profile during early pregnancy. METHODS: Data were derived from a multi-ethnic birth cohort, the Amsterdam Born Children and their Development (ABCD) study (inclusion 2003-2004). During early gestation mothers completed a questionnaire during pregnancy (pBMI) and random non-fasting blood samples were analysed for total cholesterol (TC), triglycerides (TG), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and total free fatty acids (FFA) in early gestation. At age 5-6 years, child's BMI, waist-to-height-ratio (WHtR) and fat% were assessed. RESULTS: Only non-diabetic mothers with at term-born children were included (n = 1727). Of all women, 15.1% were overweight(BMI: 25-29.9 kg/m2) and 4.3% were obese (BMI≥30 kg/m2). After adjustments for confounders, every unit increase in pBMI was linearly associated with various offspring variables: BMI (ß 0.10; 95% CI 0.08-0.12), WHtR*100 (ß 0.13; 95% CI 0.09-0.17), fat% (ß 0.21; 95% CI 0.13-0.29) and increased risk for overweight (OR:1.15; 95% CI 1.10-1.20). No convincing proof for mediation by maternal lipid profile during early gestation was found. Moreover, maternal FFA was associated with the child's fat percentage, BMI and risk for overweight. Maternal ApoB and TC were positively associated with the offspring's fat percentage and maternal TG was positively associated with their children's WHtR. CONCLUSIONS: Both pBMI and maternal lipids during early pregnancy are independently related to offspring adiposity.

The role of insulin-like growth factor during a postischemic period - new insights into pathophysiologic pathways in cardiac tissue.

Despite an improvement in the therapeutic strategies available for an acute ischemic event, cardiac disease is still the principal cause of morbidity and mortality in Western societies. A shift from acute towards more chronic heart disease due to atherosclerotic disease has been recognized. Modification of adaptive capacities of the cardiac muscle after damage remains a key component in the prevention of chronic cardiac disease, such as overt heart failure. It has recently been demonstrated that local insulin-like growth factor (IGF)-1 homeostasis in the cardiac tissue is closely involved in postischemic adaptation, such as the process of remodeling. Both experimental and clinical data support the theory that IGF-1 plays a key role in the adaptive response of the myocardium during both acute myocardial ischemia and chronic myocardial failure, regulating left ventricular remodeling and thereby restoring left ventricular architecture. This eventually leads to improvement in the function of the failing heart. While most experimental data support the beneficial role of IGF-1 in restoring architecture and function of the failing heart, clinical trials investigating the role of IGF-1 treatment of patients in cardiac failure show conflicting results. In this bench-to-bedside review, the authors aim to highlight recent advances in knowledge of the role of paracrine and autocrine IGF balances during postischemic cardiac adaptation, in order to present possible new initiatives concerning therapeutic strategies in maladaptive cardiac performance, such as the syndrome of heart failure.