Stimulation by interleukin-6 and inhibition by tumor necrosis factor of cortisol release from bovine adrenal zona fasciculata cells through their receptors

Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are synthesized and released from adrenal cells. Therefore, the effects of TNF-α and IL-6 on cortisol release from bovine zona fasciculata (ZF) cells were investigated. IL-6 (10–1000 pg/mL) significantly increased basal and adrenocorticotropic hormone (ACTH)-stimulated cortisol release in a concentration-dependent manner. This stimulatory effect of IL-6 became apparent at intervals as short as 4 h and continued through 24 h. IL-6 also potentiated the cortisol release stimulated by the adenylyl cyclase activator forskolin. By contrast, TNF-α (0.1–10 ng) inhibited basal and ACTH-stimulated cortisol release in a concentration-dependent manner. The inhibitory effects of TNF-α on cortisol release were significant at time intervals as short as 4 h and continued through 24 h. TNF-α inhibited forskolin-stimulated cortisol release. Binding studies demonstrated that ZF cells have IL-6 receptors (100 receptors/cell, K _d of 7.5×10⁻¹¹) and TNF receptors (200 receptors/cell, K _d of 2.4×10⁻⁹ M). Immunohistochemical analysis provided evidence that the majority of ZF cells have IL-6 receptors, TNF type 1 receptors, and TNF type 2 receptors. Because IL-6 and TNF-α are released from the adrenal cortex and these cytokines modify the release of cortisol from the ZF, IL-6 and TNF-α may play a paracrine or autocrine role in the regulation of adrenal function.     

Increased expression of tumor necrosis factor-alpha messenger RNA in the intestinal mucosa of inflammatory bowel disease,particularly in patients with disease in the inactive phase

Background: Background: Tumor necrosis factor-α (TNF-α), may be involved in the pathogenesis of inflammatory bowel diseases (IBDs). The aim of this study was to evaluate the effect of TNF-α on the inflammatory activity of IBD. Methods: TNF-α mRNA expression in intestinal mucosal biopsy specimens from IBD patients [ulcerative colitis (UC), n= 54; and Crohn's disease (CD), n= 11] was analyzed using a competitive polymerase chain reaction. The degree of macrophage infiltration was analyzed by immunohistochemistry, using an anti-human CD68 antibody. Results: TNF-α mRNA expression was increased in UC patients, corresponding to the inflammatory activity. However, in CD, TNF-α mRNA expression was not correlated with the endoscopic findings. Conclusions: We clarified that TNF-α mRNA expression was responsible for the inflammatory activity in UC. However, TNF-α mRNA expression was not correlated with the mucosal injury in CD. Received: February 9, 2001 / Accepted: September 28, 2001     

Biomarkers of Systemic Inflammation in Stable and Exacerbation Phases of COPD

Apart from the deleterious effects on the lungs, chronic obstructive pulmonary disease (COPD) should be considered a complex, systemic disease involving several organs and systems. The nature and course of systemic inflammation in COPD is important since there is a potential for anti-inflammatory therapy. The objective of the current study was to assess biomarkers of systemic inflammation in stable and exacerbation phases of COPD patients as compared to healthy controls. We also investigated the course of these biomarkers after COPD exacerbation to evaluate their usefulness for disease monitoring. Eighty-three stable patients with moderate to very severe COPD, 20 patients in exacerbation phase, and 30 subjects with normal pulmonary function were included. Serum tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) levels were measured once in stable COPD patients and controls and three times in the COPD exacerbation group during follow-up. TNF-α and IL-6 levels were higher than in controls in both stable and exacerbation groups. Although NO was not higher in the stable COPD group than in controls, it was higher in the exacerbation group. In follow-up after the exacerbation period, significant alteration was not detected in cytokine or NO levels compared to admission. Raised serum levels of TNF-α and IL-6 support their use as biomarkers of the systemic inflammatory response in stable COPD patients. However, the circulating biomarkers we have studied are not found to be useful either as indicators of COPD exacerbation or for monitoring recovery after exacerbation.     

The influence of improved glycaemic control with insulin and sulphonylureas on acute phase and endothelial markers in Type II Diabetic subjects

Aims/hypothesis. Improved glycaemic control might reduce both microvascular and macrovascular complications of Type II diabetes (non-insulin-dependent) mellitus. To explore such possible mechanisms, we investigated the effects of intensive treatment on markers of endothelial dysfunction and of acute phase activation, using both sulphonylureas and insulin. Methods. In a randomised cross-over study we gave sulphonylureas or insulin each for a period of 16 weeks to 22 poorly controlled Type II diabetic subjects who were being treated by diet. There was a 4 week washout period between each treatment. Subjects were studied at baseline and at the end of each treatment. Results. Treatment with sulphonylureas and insulin resulted in similar improvements in glycaemic control (glycated haemoglobin, baseline: 11.8 [(SD 2.2)%; after sulphonylureas: 8.6 (1.2)%, p < 0.001; after insulin: 8.6 (1.2)%, p < 0.001] and in insulin sensitivity {metabolic clearance rate of glucose, baseline: median 1.75 [interquartile (IQ) range 1.41, 2.27] ml · kg^–1· min^–1; after sulphonylureas: 2.41 (1.82, 3.01) ml · kg^–1· min^–1, p = 0.001; after insulin: 2.23 (1.92, 2.75) ml · kg^–1· min^–1, p = 0.027}. There were no significant changes in concentrations of endothelial markers von Willebrand factor, cellular fibronectin, thrombomodulin, tissue plasminogen activator, soluble E-selectin or soluble intercellular adhesion molecule-1 or in urinary albumin excretion rate after either treatment period. Concentrations of C-reactive protein were not significantly influenced by sulphonylureas but fell after insulin [baseline: median 4.50 (IQ range 1.37, 6.44) μg · ml^–1; sulphonylureas: 2.69 (0.88, 9.65) μg · ml^–1 (p = 0.53); insulin: 2.07 (1.16, 5.24) μg · ml^–1 (p = 0.017)]. There were, however, no significant effects of either treatment on circulating concentrations of fibrinogen (p = 0.28–0.34) or of the proinflammatory cytokines interleukin-6 or tumour necrosis factor-α (p = 0.65–0.79). Conclusion/interpretation. Markers of endothelial dysfunction and concentrations of proinflammatory cytokines in Type II diabetes are not influenced by improved glycaemic control over 16 weeks. Improved metabolic control with insulin could, however, be associated with reduced concentrations of the acute phase marker C-reactive protein. [Diabetologia (2000) 43: 1099–1106] Received: 11 May 2000 and in revised form: 19 June 2000     

Lipid hydroperoxide-induced tumor necrosis factor (TNF)-alpha, vascular endothelial growth factor and neovascularization in the rabbit cornea: effect of TNF inhibition

Lipid hydroperoxides (LHP) at high concentrations are cytotoxic, but at sublethal concentration, they induce synthesis of cytokine vascular growth factors. Intracorneal injections of 30 μg LHP placed 5 mm from the superior limbus stimulated early vasodilation of limbal vasculature and a rapidly developing, sustained neovascularization. Under these conditions, vessels grew at the rate of 0.3 mm/day to a total length of 7.5 mm, 25 days after injection. Cholesterol peroxides were less effective. Developing vessels were oriented towards the stimulus. Around the developing vessel there was dissolution of the stromal extracellular matrix. The most distal endothelial cells displayed prominent endoplasmic reticulum, a lack of basement membrane or tight junction complexes and leakage of fluorescein dye. Both the injection site and superior quadrant showed increased levels of tumor necrosis factor (TNF)-α and vascular endothelial growth factor after exposure to LHP. The neovascular response was inhibited by simultaneous administration of TNF-α antibody or pentoxifylline, an inhibitor of TNF-α synthesis. This corneal model of peroxide-induced neovascularization should prove useful for temporal studies of events in the initiation and propagation of signals leading to neovascularization, and for evaluating effects of treatment on neovascular growth. This revised version was published online in June 2006 with corrections to the Cover Date.     

High interleukin-6 production within the peritoneal cavity in decompensated cirrhosis and malignancy-related ascites

Abstract: To assess the diagnostic and prognostic value of interleukin-6, interleukin 1β, and tumor necrosis factor-α assays in plasma and ascites, we measured these cytokines in eight patients with malignancy-related ascites and 32 patients with decompensated cirrhosis. Five patients had an episode of bacterial peritonitis, during which one or more ascitic fluid samples were analyzed. Interleukin-6 and tumor necrosis factor-α were not significantly different between the cirrhotic and the malignant groups: ascitic interleukin-6 13 816±15 314 vs 28 138±23 403 pg/ml, plasma interleukin-6 542±719 vs 559±604 pg/ml; ascitic tumor necrosis factor-α 19±50 vs 12±31 pg/ml, plasma tumor necrosis factor-α 3.4±8.2 vs 6.1±13.8 pg/ml. During an episode of bacterial peritonitis there was a significant increase only in ascitic interleukin-6 (133 268±99 743 pg/ml), which declined after antibiotic treatment. None of the parameters was associated with 6-month survival (11 of the 40 patients died within 6 months). There was a correlation (r=0.675; p=0.002) between plasma interleukin-6 levels and the Child-Pugh score in patients with cirrhosis, but not with the etiology of the liver disorder. Plasma interleukin-6 levels correlated with IgA levels (r=0.649; p=0.004) but not with C reactive protein, sedimentation rate, fibrinogen, IgM or IgG. These results do suggest that interleukin-6 is produced within the peritoneal cavity in hepatic and malignant ascites. There is a sharp increase in the local production of interleukin-6 during an episode of bacterial peritonitis. This increase was not detectable for tumor necrosis factor-α. The physiological meaning of this over-production of locally generated cytokines and whether it relates to the poor prognosis of patients with cirrhosis and infectious disorders remain to be assessed.     

Cytokine inhibition in the treatment of rheumatic and inflammatory diseases

This review briefly summarizes recent information on the role of cytokines in pathophysiologic events in human rheumatic and inflammatory diseases. The major focus is on rheumatoid arthritis and on the role of interleukin (IL)-1 and tumor necrosis factor-α (TNF) in mediating synovial events of inflammation and tissue destruction. The results of clinical trials with therapeutic agents designed to inhibit the production or effects of IL-1 and TNF are reviewed. Although some of these agents show promise, more long-term studies are necessary to examine both safety and possible beneficial effects on the tissue destruction phase of the disease process.     

Hepatic stellate cells: a target for the treatment of liver fibrosis

Hepatic fibrosis is a wound-healing process that occurs when the liver is injured chronically. Hepatic stellate cells (HSC) are responsible for the excess production of extracellular matrix (ECM) components. The activation of HSC, a key issue in the pathogenesis of hepatic fibrosis, is mediated by various cytokines and reactive oxygen species released from the damaged hepatocytes and activated Kupffer cells. Therefore, inhibition of HSC activation and its related subsequent events, such as increased production of ECM components and enhanced proliferation, are crucial goals for intervention in the hepatic fibrogenesis cascade. This is especially true when the etiology is unknown or there is no established therapy for the cause of the chronic injury. This review explores the rationale for choosing HSC as a target for the pharmacological, molecular, and other novel therapeutics for hepatic fibrosis. One focus of this review is the inhibition of two cytokines, transforming growth factor-β and platelet-derived growth factor, which are important in hepatic fibrogenesis. A number of new agents, such as Chinese herbal recipes and herbal extracts, silymarin, S-adenosyl-l-methionine, polyenylphosphatidylcholine, and pentoxifylline are also discussed. Received: April 3, 2000 / Accepted: April 28, 2000     

Monocyte chemoattractant protein-1 enhances and interleukin-10 suppresses the production of inflammatory cytokines in adult rat cardiomyocytes

Objective Chemokines control the migration of leukocytes to inflamed tissue, and in particular monocyte chemoattractant protein (MCP)-1 has been implicated in the pathogenesis of several cardiovascular disorders such as chronic heart failure (CHF) and myocarditis. We hypothesised that MCP-1 may directly contribute to an inflammatory response in the cardiomyocytes, and in the present study we examined in adult rat cardiomyocytes: (i) the effect of tumour necrosis factor (TNF)a on MCP-1 production, (ii) the effect of MCP-1 on production of other inflammatory cytokines, and (iii) if the anti-inflammatory cytokine interleukin (IL)-10 could suppress any TNFα-induced MCP-1 production. Methods We used enzyme immunoassays, RNase protection assays and slot blot analysis to measure protein and mRNA levels of various cytokines in adult rat cardiomyocyte cultures. Results (i) We found a ∼6.4-fold increase of the MCP-1 level accompanied by an increase in MCP-1 mRNA accumulation in cardiomyocyte cultures after TNFα stimulation. (ii) In contrast, TNFα had no effect on IL-10 and only a modest effect on IL-1β and IL-6 levels in these cells. (iii) Importantly, MCP-1 stimulated inflammatory response in cardiomyocytes by enhancing IL-1β and IL-6 levels in these cells as found at both the protein and mRNA level. (iv) Co-stimulation with IL-10 resulted in a ∼55 % reduction in TNFα-stimulated MCP-1 levels in cardiomyocyte culture supernatants. Conclusion The present study demonstrates for the first time that MCP-1 can directly affect cardiomyocytes, and we introduce MCP-1 as a potential enhancer and IL-10 as a potential suppresser of inflammatory responses within the myocardium. Received: 10 October 2000 / Returned for 1. revision: 2 November 2000 / 1. Revision received: 5 December 2000 / Returned for 2. revision: 2 January 2001 / 2. Revision received: 5 January 2001 / Accepted: 8 January 2001     

Moderate calorie restriction improves cardiac remodeling and diastolic dysfunction in the Dahl-SS rat

Caloric restriction extends longevity and reduces the onset of chronic disease in many animal models. Recently, caloric restriction was shown in humans to be associated with lower blood pressure, decreased systemic inflammation, and improved cardiac diastolic parameters. However, the causation and mechanisms of caloric restriction were obscured by the varied diet composition of the participants. The Dahl salt-sensitive rat which develops gradual, hypertension-associated diastolic dysfunction was used in this study to assess the impact of caloric restriction upon decompensated pressure-overload hypertrophy. Male Dahl salt-sensitive rats were provided either a low-salt diet or a high-salt diet to initiate heart failure progression. A further subset of high-salt rats underwent 15% calorie restriction, with salt load held constant. Parameters measured included serial systolic blood pressure, body weight, and changes of left ventricular systolic and diastolic parameters and ventricular geometry by echocardiography. After 18 weeks, fasting glucose, blood lipids, heart weight, kidney weight, lung weight, plasma interleukin-6 and TNF-alpha, and cardiac lipid peroxidation were measured. Low-salt rats did not develop heart failure. While high-salt rats displayed features of decompensated pressure-overload hypertrophy, moderate calorie restriction remarkably reduced morbidity. Compared to the high-salt fed group, the high-salt, calorie-restricted group showed reduced blood pressure, delayed onset of cachexia, lower fasting hyperlipidemia, lower cardiac, renal and lung weight, less plasma IL-6 and TNF-alpha, less cardiac oxidative damage, and improved diastolic chamber function and cardiac index. Modest calorie restriction, independent of salt intake, reduced pathogenesis in this well described model of decompensated pressure-overload hypertrophy.     

The role of low-grade inflammation in the polycystic ovary syndrome

PCOS is not only the most frequent cause of oligomenorrhea in young women, but also a metabolic disorder characterized by insulin resistance, glucose intolerance, dyslipidemia, and obesity, especially the visceral phenotype. PCOS represents a broad spectrum of endocrine and metabolic alterations which change with age and with increasing adiposity. In fact, during adolescence and youth the predominant clinical manifestations of PCOS are menstrual abnormalities, hirsutism and acne, whereas in peri-menopausal and post-menopausal periods metabolic disorders and an increased risk for cardiovascular diseases prevail. The pathogenetic links between PCOS and metabolic or cardiovascular complications are still debated. However, recent evidence has been focused on a condition of low-grade chronic inflammation as a potential cause of the long-term consequence of the syndrome.