Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multicentric Castleman disease (MCD) is an atypical lymphoproliferative disorder characterized by systemic lymphadenopathy and constitutional inflammatory symptoms. Dysregulated overproduction of interleukin-6 is responsible for the clinical abnormalities. This multicenter prospective study was undertaken to evaluate the safety and efficacy of a humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody (MRA) in patients with MCD. We report here results of the first 60 weeks of the study enrolling 28 patients. The initial dosing period consisted of 8 infusions of 8 mg/kg MRA administered biweekly. Adjustments in the dose and treatment interval were allowed for each patient in an extension phase after 16 weeks. Within 16 weeks, treatment with MRA consistently alleviated lymphadenopathy and all the inflammatory parameters. Hemoglobin, albumin, and total cholesterol levels, high-density lipoprotein cholesterol values, and body mass index all increased significantly. In addition, fatigue diminished. Chronic inflammatory symptoms were successfully managed over 60 weeks. In 8 (28.6%) patients, the MRA dose was decreased or the treatment interval was extended without exacerbation. Eleven (73.3%) of 15 patients who had received oral corticosteroids before study entry were able to do well on a reduced corticosteroid dose. Most adverse events were mild to moderate in severity. MRA was tolerated well and significantly alleviated chronic inflammatory symptoms and wasting in patients with MCD.
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PMID:Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. 1599 37

Cardiovascular disease remains a major cause of morbidity and mortality in end-stage renal disease patients. As traditional risk factors cannot alone explain the unacceptable high prevalence and incidence of cardiovascular disease in this high-risk population, inflammation (interrelated to insulin resistance, oxidative stress, wasting and endothelial dysfunction) has been suggested to be a significant contributor. Recent studies show that the adipose tissue is a complex organ with functions far beyond the mere storage of energy. Indeed, it has been shown that fat tissue secretes a number of adipokines including leptin, adiponectin and visfatin, as well as a cytokines (here defined as signaling proteins mainly secreted by other cells present in adipose tissue, but sometimes also to a lesser degree by adipocytes per se), such as resistin, tumor-necrosis factor-alpha and interleukin-6. Adipokine serum levels are markedly elevated in chronic kidney disease, probably due to decreased renal excretion. Evidence suggests that they may have pro-inflammatory effects as well as contribute to metabolic derangements. Much research is thus still needed to elucidate the likely complex interactions between different fat tissue depots, muscle tissue and its' effects on inflammation, vascular health and outcome in this high-risk population.
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PMID:Adipose tissue and inflammation in chronic kidney disease. 1692 40

Clinical wasting is an important risk factor for mortality in uremic patients and is reported to have a prevalence of 30-60%. 'Malnutrition' is often inappropriately used to describe a group of nutritional abnormalities in uremic patients, which are characterized by anorexia, increased basal metabolic rate, loss of lean body mass, and declining levels of serum proteins. This syndrome--more accurately described as 'cachexia'--manifests as growth failure in children with uremia. Acidosis and inflammation are important causes of uremic cachexia but the underlying molecular mechanism is not well understood. Concentrations of circulating cytokines, such as leptin, tumor necrosis factor-alpha, interleukin-1, and interleukin-6, are elevated in patients with end-stage renal disease and correlate with the degree of cachexia in these individuals. Other energy-modulating hormones such as ghrelin, and adipokines such as adiponectin and resistin, are also perturbed in uremia and could contribute to nutritional abnormalities. We recently showed that elevated levels of circulating cytokines might be an important contributor to uremia-associated cachexia via signaling through the central melanocortin system. Small-molecule melanocortin antagonists, which are biologically active when administered orally or intraperitoneally, are now available and have been used successfully to ameliorate experimental cachexia. These findings could form the basis of a novel therapeutic strategy for uremic cachexia.
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PMID:Mechanisms of disease: Cytokine and adipokine signaling in uremic cachexia. 1694 Oct 45

In the treatment of rheumatic diseases such as rheumatoid arthritis (RA) or systemic onset juvenile idiopathic arthritis (soJIA), new therapies targeting pro-inflammatory cytokines have been developed. IL-6 is a pleiotropic cytokine with a wide range of biological activities including a pro-inflammatory mediator activity. Overproduction of IL-6 has been reported to be pathologically involved in the rheumatic diseases and, therefore, blockade of IL-6 actions may improve the disease. Tocilizumab, a humanized monoclonal antibody against human interleukin-6 receptor (IL-6R), inhibits IL-6 binding to IL-6R and specifically interferes with IL-6 actions. Castleman's disease is an atypical lymphoproliferative disorder caused by the overproduction of IL-6. Tocilizumab therapy improves immunological and hematological abnormalities as well as systemic inflammatory symptoms including wasting. This translational study also confirmed the pathological significance of IL-6 in the disease. RA is a representative autoimmune inflammatory disease characterized by bone and cartilage destruction in multiple joints. Since IL-6 also plays pathological roles in RA, tocilizumab therapy has been introduced to the patients with refractory disease and has shown a strong therapeutic effect. Besides Castleman's disease and RA, tocilizumab has been shown to be effective for patients with soJIA and Crohn's disease. Tocilizumab treatment is generally well tolerated and safe. Therefore, tocilizumab can be a promising therapeutic agent for the rheumatic diseases in which IL-6 overproduction is pathologically involved.
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PMID:Anti-interleukin-6 receptor antibody therapy in rheumatic diseases. 1721 83

The hypertriglyceridemia of infection is produced by many of the cytokines that regulate the immune response, including the tumor necrosis factors, interleukin-1, interleukin-6, and the interferons. In rodents, this hypertriglyceridemia is primarily due to the ability of these cytokines to stimulate hepatic lipogenesis and very low density lipoprotein production without causing significant changes in adipose tissue lipoprotein lipase or triglyceride clearance. Induction of hypertriglyceridemia is not directly linked to the syndrome of wasting. Rather, the increase in hepatic production of lipoproteins is part of the acute-phase response and may contribute to host defense.
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PMID:Tumor necrosis factor, cytokines, and the hyperlipidemia of infection. 1841 Nov 85

As the kidney is the major site for elimination of many cytokines, the delicate equilibrium of pro-inflammatory cytokines and their inhibitors is clearly dysregulated in chronic kidney disease (CKD) patients. The consequences of the altered immune response in uremia lead to a state of persistent inflammation which is highly prevalent among CKD patients and is linked to complications such as the development of protein-energy wasting and atherosclerotic vascular disease. The present review aims at reviewing this complex orchestration of uremic cytokines beyond the well-studied interleukin-6 and tumor necrosis factor-alpha. Finally, we update our current understanding on anti-inflammatory treatment strategies in CKD patients, including nutritional and lifestyle measurements, pharmacological intervention and specific anticytokine strategies targeting the dialytic procedure.
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PMID:Cytokine dysregulation in chronic kidney disease: how can we treat it? 1842 Dec 14

Interleukin-6 (IL-6) is necessary for cachexia in Apc ( Min/+ ) mice, but the mechanisms inducing this myofiber wasting have not been established. The purpose of this study was to examine gastrocnemius muscle wasting in the Apc ( Min/+ ) mouse and to determine IL-6 regulated mechanisms contributing to muscle loss. Gastrocnemius type IIB mean fiber cross-sectional area (CSA) from Apc ( Min/+ ) mice decreased 32% between 13 and 22 weeks of age. Apc ( Min/+ ) mice lacking IL-6 did not have type IIB fiber atrophy, while overexpression of circulating IL-6 exacerbated the loss of type IIB fiber CSA in Apc ( Min/+ ) mice. Muscle Atrogin-I mRNA expression was induced at least ninefold at 18 and 22 weeks of age compared to 13-week-old mice. Atrogin-I gene expression was also induced by overexpression of circulating IL-6. These data suggest that high circulating IL-6 levels induce type IIB fiber CSA loss in Apc ( Min/+ ) mice, and circulating IL-6 is sufficient to regulate Atrogin-I gene expression in cachectic mice.
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PMID:Muscle wasting and interleukin-6-induced atrogin-I expression in the cachectic Apc ( Min/+ ) mouse. 1871 12

The stress and inflammatory responses to burn injury are associated with bone loss. The stress response entails production of large amounts of endogenous glucocorticoids that decrease osteoblasts on the mineralization surface of bone and decreases differentiation of marrow stromal cells into osteoblasts, thereby decreasing the amount of bone formation. Deficiency of osteoblasts also blocks osteoclastogenesis thus leading to low bone turnover and bone loss. The inflammatory response generates cytokines such as interleukin 1-beta and interleukin-6, which normally increase osteoclastogenic bone resorption via stimulation of osteoblast production of RANK ligand. However, in the absence of osteoblasts as a target we postulate that they attack the parathyroid gland chief cells and up-regulate the calcium-sensing receptor. The consequence of this upregulation is the lowering of the circulating calcium necessary to suppress parathyroid hormone production and the development of hypocalcemia and urinary calcium wasting. It is the parathyroid hormone suppression that causes us to postulate acute deficiency of 1,25-dihydroxyvitamin D and the consequence of this for post-burn metabolism could include derepression of the gene that controls renin production, leading to elevated levels of angiotensin II, which can contribute to insulin resistance, as can vitamin D deficiency itself. Moreover, the skin from burned patients cannot synthesize vitamin D normally. Thus vitamin D supplementation is the only means by which to ensure vitamin D sufficiency for burn victims. The proper requirement for vitamin D in acutely burned patients remains unknown.
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PMID:The interaction between burn injury and vitamin D metabolism and consequences for the patient. 1878 7

Serum transferrin, estimated by total iron-binding capacity (TIBC), may be a marker of protein-energy wasting (PEW) in maintenance hemodialysis (MHD) patients. We hypothesized that low TIBC or its fall over time is associated with poor clinical outcomes. In 807 MHD patients in a prospective 5-year cohort, associations of TIBC and its changes over time with outcomes were examined after adjustment for case-mix and markers of iron stores and malnutrition-inflammation including serum interleukin-6, iron and ferritin. Patients with serum TIBC >or=250 mg/dl had higher body mass index, triceps and biceps skinfolds and mid-arm muscle circumference and higher serum levels of iron but lower ferritin and inflammatory markers. Some SF-36 quality of life (QoL) components were worse in the lowest and/or highest TIBC groups. Mortality was incrementally higher in lower TIBC levels (p-trend <0.001). Adjusted death hazard ratio was 1.75 (95% CI: 1.00-3.05, p = 0.05) for TIBC <150 compared to TIBC of 200-250 mg/dl. A fall in TIBC >20 mg/dl over 6 months was associated with a death hazard ratio of 1.57 (95% CI: 1.04-2.36, p = 0.03) compared to the stable TIBC group. Hence, low baseline serum TIBC is associated with iron deficiency, PEW, inflammation, poor QoL and mortality, and its decline over time is independently associated with increased death risk.
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PMID:Association of serum total iron-binding capacity and its changes over time with nutritional and clinical outcomes in hemodialysis patients. 1913 18

In individuals with advanced chronic kidney disease, secondary hyperparathyroidism is known to be associated with high turnover bone disease. Low serum parathyroid hormone (PTH) levels may not necessarily be because of hypodynamic bone, but could be another facet of the malnutrition-inflammation-cachexia syndrome (MICS). A recent 5-year cohort study in 748 stable hemodialysis outpatients showed that after the confounding effect by the MICS was removed, the moderately low levels of PTH in the 100 to 150 pg/mL range was associated with the greatest survival rate. Data from Japanese dialysis patients show similar survival advantages of having a lower PTH range. Low levels of serum PTH seem to be associated with markers of protein-energy wasting and inflammation, and this association may confound the relationship between serum PTH and alkaline phosphatase. PTH stimulates lipogenesis through influx of calcium into the adipocytes. PTH secretion is suppressed by interleukin-1 beta and interleukin-6, which are proinflammatory cytokines that are associated with poor outcome in dialysis patients. These cytokines inhibits PTH secretion in cultured parathyroid tissue slices. In this article, we review the association of a low serum PTH level with the MICS in patients with chronic kidney disease and suggest avoiding over-interpretation of low serum PTH level as an indicator of low turnover bone disease.
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PMID:Insights into nutritional and inflammatory aspects of low parathyroid hormone in dialysis patients. 2119 29


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