In previous publications, we presented the hypothesis that repeated episodes of acute or chronic psychological stress could induce an acute phase response (APR) and subsequently a chronic inflammatory process such as atherosclerosis. In this paper, that hypothesis, namely that such stress can induce an APR and inflammation, has been extended to include a chronic inflammatory process(s), characterized by the presence of certain cytokines and acute phase reactants (APR), which is associated with certain metabolic diseases. The loci of origin of these cytokines, particularly interleukin 6 (IL-6), and their induction, has been considered. Evidence is presented that the liver, the endothelium, and fat cell depots are the primary sources of cytokines, particularly IL-6, and that IL-6 and the acute phase protein (APP), C-reactive protein (CRP), are strongly associated with, and likely play a dominant role in, the development of this inflammatory process which leads to insulin resistance, non-insulin dependent diabetes mellitus type II, and Metabolic syndrome X. The possible role of psychological stress and the major stress-related hormones as etiologic factors in the pathogenesis of these metabolic diseases, as well as atherosclerosis, is discussed. The fact that stress can activate an APR, which is part of the innate immune inflammatory response, is evidence that the inflammatory response is contained within the stress response or that stress can induce an inflammatory response. The evidence that the stress, inflammatory, and immune systems all evolved from a single cell, the phagocyte, is further evidence for their intimate relationship which almost certainly was maintained throughout evolution.

The inflammatory response is an integral part of the stress response: Implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X.

Interleukin-6 (IL-6) synthesized in response to diverse stimuli may play an important role in bridging the inflammatory and atherosclerotic processes. The acute-phase response after coronary artery bypass graft surgery (CABG) is associated with the induction and release of cytokines, such as IL-6. We have examined the effect of common polymorphisms in the IL-6 gene promoter (−174G>C, −572G>C, and −597G>A) on IL-6 levels after elective CABG. DNA extracted from the peripheral blood of 127 patients was amplified by polymerase chain reaction. IL-6 genotypes were resolved by gel electrophoresis after restriction enzyme digestion. Serum IL-6 was measured before surgery and in serial samples at 6, 24, 48, and 72 hours after CABG. Genotype distribution was as expected for a population in Hardy-Weinberg equilibrium for all polymorphisms. Rare allele frequencies (±95% CIs) were similar to those reported previously: −597A 0.36 (0.30 to 0.42), −572C 0.07 (0.04 to 0.10), and −174C 0.37 (0.31 to 0.43). The −174G>C and −597G>A genotypes were in strong allelic association (Δ=0.97, P P =0.03) in carriers of the −572C allele than in those of the −572GG genotype (355±67 versus 216±13 pg/mL, respectively) and in those with genotype −174CC compared with −174G allele carriers (287±31 versus 227±15 pg/mL, respectively; P =0.04). These effects remained statistically significant after adjusting for possible confounders, including age, sex, smoking, duration of cardiopulmonary bypass, aortic cross-clamp time, and total duration of surgery. These data demonstrate that IL-6 promoter polymorphisms influence peak IL-6 production after CABG, suggesting that these polymorphisms, which are functional in vitro, are also functional in vivo, suggesting a genetic influence on IL-6 levels after acute severe injury.

Interleukin-6 Gene −174G>C and −572G>C Promoter Polymorphisms Are Strong Predictors of Plasma Interleukin-6 Levels After Coronary Artery Bypass Surgery

Caffeic acid (CA) and ellagic acid (EA) are phenolic acids naturally occurring in many plant foods. Cardiac protective effects of these compounds against dyslipidemia, hypercoagulability, oxidative stress and inflammation in diabetic mice were examined. Diabetic mice were divided into three groups (15 mice per group): diabetic mice with normal diet, 2% CA treatment, or 2% EA treatment. One group of non-diabetic mice with normal diet was used for comparison. After 12 weeks supplement, mice were sacrificed, and the variation of biomarkers for hypercoagulability, oxidative stress and inflammation in cardiac tissue of diabetic mice were measured. The intake of CA or EA significantly increased cardiac content of these compounds, alleviated body weight loss, elevated plasma insulin and decreased plasma glucose levels in diabetic mice (p < 0.05). These treatments also significantly enhanced plasma antithrombin-III and protein C activities (p < 0.05); and decreased triglyceride content in cardiac tissue and plasma (p < 0.05), in which the hypolipidemic effects of EA were significantly greater than that of CA (p < 0.05). CA or EA significantly lowered cardiac levels of malondialdehyde, reactive oxygen species, interleukin (IL)-beta, IL-6, tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein (MCP)-1 (p < 0.05); and retained cardiac activity of glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase (p < 0.05). These compounds also significantly up-regulated cardiac mRNA expression of GPX1, SOD and catalase; and down-regulated IL-1beta, IL-6, TNF-alpha and MCP-1 mRNA expression in diabetic mice (p < 0.05). These results support that CA and EA could provide triglyceride-lowering, anti-coagulatory, anti-oxidative, and anti-inflammatory protection in cardiac tissue of diabetic mice. Thus, the supplement of these agents might be helpful for the prevention or attenuation of diabetic cardiomyopathy.

/pdf/anti-inflammatory-and-anti-coagulatory-activities-of-caffeic-2tcfe5dryi.pdf

Anti-inflammatory and anti-coagulatory activities of caffeic acid and ellagic acid in cardiac tissue of diabetic mice

Lifestyle-only intervention attenuates the inflammatory state associated with obesity: A randomized controlled study in adolescents

Obesity is increasingly prevalent and is associated with substantial cardiovascular risk. Adipose tissue distribution and morphology play a key role in determining the degree of adverse effects, and a key factor in the disease process appears to be the inflammatory cell population in adipose tissue. Healthy adipose tissue secretes a number of vasoactive adipokines and anti-inflammatory cytokines, and changes to this secretory profile will contribute to pathogenesis in obesity. In this review, we discuss the links between adipokine dysregulation and the development of hypertension and diabetes and explore the potential for manipulating adipose tissue morphology and its immune cell population to improve cardiovascular health in obesity.

/pdf/mechanistic-links-between-obesity-diabetes-and-blood-24pbz8jz9c.pdf

Mechanistic Links Between Obesity, Diabetes, and Blood Pressure: Role of Perivascular Adipose Tissue.

Objectives. To investigate the regulation of soluble adhesion molecules by tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and relationships with circulating cytokine receptors, in vivo, in type 1 diabetes.Design. Cross-sectional study.Setting. University hospital diabetes clinic.Subjects. A total of 47 non-nephropathic, Caucasian type 1 diabetics and 39 nondiabetic controls.Outcome measures. Plasma levels of TNF-alpha, IL-6, their soluble receptors and adhesion molecules intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), sE-selectin and von Willebrand factor (vWF), and risk factors for cardiovascular disease.Results. Plasma concentrations of IL-6 were elevated in diabetic patients compared with controls [median (interquartiles) 1.28 (0.89-2.65) vs. 0.66 (0.45-1.73) pg mL(-1): P=0.016], and in these patients IL-6 and soluble IL-6 receptor (sIL-6R) levels correlated with concentrations of sICAM-1 (r=0.41, P=0.012 and r=0.31, P =0.04, respectively), Tumour necrosis factor-a soluble receptor-2 (sTN-FRII), but not TNF-alpha or tumour necrosis factor soluble receptor-1 (sTNFRI), was elevated in diabetic subjects (P=0.027). Plasma TNF-alpha levels correlated with sVCAM-1 (r=0.39, P=0.008), triglycerides (r=0.36, P=0.021) and diastolic blood pressure (r=0.35; P=0.024). Both sTNFRI and sTNFRII correlated with blood pressure (r=0.46, P=0.002; r=0.32, P=0.034) and triglycerides (r=0.33, P=0.033; r=0.29, P=0.05). In contrast, HDL-cholesterol and triglyceride were related to sE-selectin (r = -0.45 and +0.45; both P and sIL-6R correlated sTNFRI and RII (r = 0.44-0.49, P are associated with dyslipidaemia and increased blood pressure, adding to vascular disease risk; (iii) the actions of both cytokines are probably modified by altered production of soluble receptors in diabetic subjects.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2796.2001.00900.x

Evidence for the regulation of levels of plasma adhesion molecules by proinflammatory cytokines and their soluble receptors in type 1 diabetes.

Objectives: To investigate the effects of β-adrenergic stimulation on IL-6 secretion in humans, and to determine the potential contribution to this response of adipocytes and peripheral blood cells (PBC). Design: Experimental study in 8 human volunteers, and in vitro studies on murine adipocyte cell-line, 3T3.L1 and 3T3.F442A, and human PBC. Measurements: Plasma IL-6 and TNFα responses to isoprenaline infusion. Cytokine secretion from differentiated adipocyte cell-lines and PBC in response to isoprenaline. Results: Plasma IL-6 levels increased ninefold (median) by 180 min (baseline median 0.51 [interquartile range 0.47–1.4] vs 180 mins 4.53 [2.58–5.69] pg ml−1, P=0.01). One hour after infusion, IL-6 levels (2.9 [1.27–3.98]) were lower than at 180 min (P=0.05), but higher than baseline (P=0.01). TNFα levels were unchanged. Differentiated adipocytes incubated in isoprenaline (0–0.1 μM) released significantly increased amounts of IL-6 whereas no response was elicited from PBC. Conclusions: The induction of IL-6 observed in vivo may be attributed to the β-adrenergic stimulation of IL-6 release specifically from adipocytes, as opposed to circulating blood cells.

β-Adrenergic regulation of proinflammatory cytokines in humans

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Evidence for the regulation of levels of plasma adhesion molecules by proinflammatory cytokines and their soluble receptors in type 1 diabetes.

β-Adrenergic regulation of proinflammatory cytokines in humans