Human interleukin-27: wide individual variation in plasma levels and complex inter-relationships with interleukin-17A.

Although it is widely believed that interleukin (IL)-27 is anti-inflammatory, its role in controlling human immune responses is not fully established. In particular, its interactions with T helper type 17 (Th)17 cytokines are unclear. Our aims were to establish the relationships between IL-27 and proinflammatory cytokines, including IL-17A, in human sera and cultures of peripheral blood mononuclear cells. Plasma IL-27 levels in 879 healthy humans from 163 families varied widely, but with relatively low heritability (19%). Despite IL-27 including a subunit encoded by Epstein-Barr virus-induced gene 3 (EBI3), there was no correlation of levels with serological evidence of infection with the virus. Although IL-27 has been reported to inhibit IL-17A production, we demonstrated a strong positive correlation in sera, but lower correlations of IL-27 with other proinflammatory cytokines. We verified that IL-27 inhibited IL-17A production by human peripheral blood T cells in vitro, but not that it stimulated IL-10 secretion. Importantly, addition of IL-17A decreased IL-27 production by stimulated T cells but had the opposite effect on resting T cells. Together, these data suggest a model whereby IL-27 and IL-17A exerts complex reciprocal effects to boost inflammatory responses, but restrain resting cells to prevent inappropriate activation.

Common variation in the adiponectin gene has an effect on systolic blood pressure.

The genotype at the C-11377G single-nucleotide polymorphism (SNP) (rs266729) in the adiponectin gene promoter has been shown to affect the prevalence of coronary atherosclerosis and incidence of vascular events in men, and to affect carotid intima media thickness. We have examined the relationship between this polymorphism and blood pressure in a cohort ascertained to express variability in blood pressure measurements. We studied a cohort of 255 families comprising 1425 individuals ascertained via a hypertensive proband. Blood pressure was measured by ambulatory monitoring. The C-11377G SNP was genotyped using a TaqMan assay. There was evidence of association between this SNP and log systolic blood pressure (SBP), having adjusted for significant covariates including gender, age and drug treatment; P=0.009, 0.014 and 0.022, respectively, for daytime, night-time and clinic measurements. Replacing C by G caused an increase of 1.63, 1.83 and 1.61%, respectively, per gene copy. There were smaller effects on diastolic blood pressure and waist-hip ratio, which were of borderline significance. Genotype at the C-11377G (rs266729) polymorphism has independent effects both on waist-hip ratio and SBP. This may help in understanding the complex role that the adiponectin gene has in atherosclerosis.

Fresh fields and pathways new: recent genetic insights into cardiac malformation.

Cardiovascular malformations are the most common type of birth defect. Currently, only a fraction of cases have associated causative factors and little is known about the aetiology of the rest. Despite this, our understanding of normal and abnormal heart development continues to grow, a number of recent discoveries even challenging long-held concepts. In this review, we highlight some of this new knowledge, emphasising aspects that may be of interest to the clinician.

Local vessel injury following percutaneous coronary intervention does not promote early mobilisation of endothelial progenitor cells in the absence of myocardial necrosis.

BACKGROUND/OBJECTIVES: Endothelial progenitor cells (EPCs) are circulating mononuclear cells that are released from the bone marrow in response to injury and participate in vascular repair. Some previous studies have suggested an early mobilisation of EPCs following percutaneous coronary intervention (PCI) that could modulate the subsequent risk of restenosis or stent thrombosis. However, those studies did not discriminate between vascular injury caused by PCI and any associated myocardial injury. Myocardial injury alone can influence EPC mobilisation in a non-specific manner, and could therefore confound any association with risk. We investigated the effect of local endothelial trauma following PCI on EPC mobilisation in the absence of myocyte necrosis. DESIGN: We quantified circulating EPCs from 20 patients immediately before, 6 hours and 24 hours following elective PCI in patients without a 24-hour troponin rise. Absolute counts of EPCs expressing combinations of CD45, CD34, CD133 and kinase domain receptor (KDR) were recorded using flow cytometry. RESULTS: There was a fall of 7-15% in EPC numbers between baseline and 6 hours post procedure and a subsequent rise (5-18%) from 6 hours to 24 hours. At 24 hours EPC levels were similar to baseline. CONCLUSIONS: The specific localised vascular injury induced by PCI did not lead to early mobilisation of EPCs. However, the fall in EPCs 6 hours after PCI was significant and its relation to early post-PCI complications such as stent thrombosis requires further exploration.

Circulating endothelial progenitor cell numbers are not associated with donor organ age or allograft vasculopathy in cardiac transplant recipients.

INTRODUCTION: Increasing age is associated with reduced numbers of circulating endothelial progenitor cells (EPCs). It is unclear whether this relates to depletion or impairment of bone marrow progenitors, or to deficient mobilization signals from aging tissues. In cardiac transplant patients, one previous study has reported an association between circulating EPCs and the risk of cardiac allograft vasculopathy (CAV). We investigated whether increased donor heart age, a strong risk factor for CAV, was associated with reduced circulating EPC numbers in a group of cardiac transplant recipients matched for factors which influence EPC numbers, but with maximally discordant donor heart ages. METHODS: We identified 32 patient pairs, matched for factors known to influence EPC numbers, but who had discordant donor heart ages by at least 20 years. EPCs were quantified using flow cytometry for absolute counts of cells expressing all the combinations of CD45, CD34, CD133 and the kinase domain receptor (KDR). RESULTS: There were no significant differences in the numbers of circulating EPCs between patients with old or young donor heart age. There was no association between the presence of CAV and circulating EPC numbers. CONCLUSIONS: We suggest that the increased susceptibility to CAV of older donor hearts is not mediated via circulating EPCs. Our results are consistent with the theory that the normal age-related decline in EPC numbers relates to bone marrow aging rather than failure of target tissues to induce EPC mobilization.

UK prospective diabetes study (UKPDS) 14: association of angiotensin-converting enzyme insertion/deletion polymorphism with myocardial infarction in NIDDM.

The deletion allele of the insertion/deletion polymorphism of the angiotensin-converting enzyme gene has been suggested to be an independent risk factor for myocardial infarction, particularly in subjects judged to be "low-risk" by the criteria of lipid status and body mass index. In a prospective, matched case-control study, we have investigated the role of this polymorphism as a risk factor for myocardial infarction in 173 newly-diagnosed British Caucasian non-insulin-dependent diabetic subjects taken from the United Kingdom Prospective Diabetes Study who subsequently developed myocardial infarction and 297 control subjects from the same study population matched for known cardiovascular risk factors including age at diagnosis of diabetes, gender, blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride and smoking habit. A trend towards increased risk conferred by homozygosity for the deletion allele was observed in cases (odds ratio 1.63, p = 0.09). When the population was stratified according to the matched risk factors, the deletion allele was associated with myocardial infarction in those with low plasma low-density lipoprotein cholesterol (odds ratio 3.67, p = 0.002), or low triglyceride (odds ratio 3.14, p = 0.005). The strongest association of the deletion allele with myocardial infarction was observed in subjects with both low low-density lipoprotein cholesterol and low triglyceride levels (odds ratio 9.0, p < 0.001). These results show that the deletion allele is a risk factor for myocardial infarction in non-insulin-dependent diabetic patients who have a favourable lipid profile.