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• W2016451005 abstract "To examine if uremia influences muscle interleukin-6 (IL-6) metabolism we studied the exchange of IL-6 across the forearm in 16 patients with chronic kidney disease (CKD) (stages 3 and 4), in 15 hemodialysis (HD)-treated end-stage renal disease (ESRD) patients (n=15), and in six healthy controls. In addition, we performed an analysis of both IL-6 protein and IL-6 mRNA expression in muscle of CKD (stage 4) patients showing evidence of inflammation and in controls. A release of IL-6 from the forearm was observed in patients with elevated IL-6 plasma levels. Arterial IL-6 was directly related to released IL-6 (r=0.69; P<0.004) in HD patients. Both IL-6 protein and IL-6 mRNA expression were increased in muscle of inflamed CKD patients vs controls (P<0.05). Although muscle net protein balance was similar in all patients, it was significantly more negative in HD patients with high than in those with low IL-6 plasma levels (P<0.05). In addition, net protein balance was related to the forearm release of IL-6 in HD patients only (r=0.47; P<0.038). These data demonstrate that IL-6 expression is upregulated in muscle, and that muscle tissue, by releasing this cytokine, may contribute to the inflammatory response in HD patients. The release of IL-6 from peripheral tissues is associated with an increase in muscle protein loss in HD patients, suggesting that muscle release of IL-6 is linked to protein catabolism in these patients. The release of IL-6 from peripheral tissues may act as a signal for the inflammatory response and contribute to functional dysregulation in uremia. To examine if uremia influences muscle interleukin-6 (IL-6) metabolism we studied the exchange of IL-6 across the forearm in 16 patients with chronic kidney disease (CKD) (stages 3 and 4), in 15 hemodialysis (HD)-treated end-stage renal disease (ESRD) patients (n=15), and in six healthy controls. In addition, we performed an analysis of both IL-6 protein and IL-6 mRNA expression in muscle of CKD (stage 4) patients showing evidence of inflammation and in controls. A release of IL-6 from the forearm was observed in patients with elevated IL-6 plasma levels. Arterial IL-6 was directly related to released IL-6 (r=0.69; P<0.004) in HD patients. Both IL-6 protein and IL-6 mRNA expression were increased in muscle of inflamed CKD patients vs controls (P<0.05). Although muscle net protein balance was similar in all patients, it was significantly more negative in HD patients with high than in those with low IL-6 plasma levels (P<0.05). In addition, net protein balance was related to the forearm release of IL-6 in HD patients only (r=0.47; P<0.038). These data demonstrate that IL-6 expression is upregulated in muscle, and that muscle tissue, by releasing this cytokine, may contribute to the inflammatory response in HD patients. The release of IL-6 from peripheral tissues is associated with an increase in muscle protein loss in HD patients, suggesting that muscle release of IL-6 is linked to protein catabolism in these patients. The release of IL-6 from peripheral tissues may act as a signal for the inflammatory response and contribute to functional dysregulation in uremia. Several studies have shown a strong association between chronic inflammation and long-term mortality and morbidity in patients with end-stage renal disease (ESRD).1.Bergstrom J. Lindholm B. Malnutrition, cardiac disease, and mortality: an integrated point of view.Am J Kidney Dis. 1998; 32: 834-841Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 2.Kaysen G.A. The microinflammatory state in uremia: causes and potential consequences.J Am Soc Nephrol. 2001; 12: 1549-1557PubMed Google Scholar The percentage of patients showing evidence of inflammation increases progressively along with the decline in renal function, suggesting that cell release and/or body removal of pro-inflammatory cytokines is altered by uremia.3.Eustace J.A. Astor B. Muntner P.M. et al.Prevalence of acidosis and inflammation and their association with low serum albumin in chronic kidney disease.Kidney Int. 2004; 65: 1031-1040Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar Interleukin-6 (IL-6) is a major factor coordinating the acute-phase response4.Heinrich P.C. Castell J.V. Andus T. Interleukin-6 and the acute-phase response.Biochem J. 1990; 265: 621-636Crossref PubMed Scopus (2194) Google Scholar and plasma levels of IL-6 are associated with increased cardiovascular risk5.Ridker P.M. Rifai N. Pfeffer M. et al.Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction.Circulation. 2000; 101: 2149-2153Crossref PubMed Scopus (792) Google Scholar and loss of muscle mass,6.Bermudez E.A. Rifai N. Buring J. et al.Interrelationships among circulating interleukin-6, C-reactive protein, and traditional cardiovascular risk factors in women.Arterioscler Thromb Vasc Biol. 2002; 22: 1668-1673Crossref PubMed Scopus (344) Google Scholar both in the general population and in ESRD patients.7.Stenvinkel P. Barany P. Heimburger O. et al.Mortality, malnutrition, and atherosclerosis in ESRD: what is the role of interleukin-6?.Kidney Int Suppl. 2002; 80: 103-108Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar However, sites and mechanisms responsible for the regulation of circulating IL-6 and other cytokines in humans are currently poorly known. Although most of the circulating IL-6 is secreted from activated macrophages and lymphocytes, adipocytes8.Mohamed-Alì V. Goodrick S. Rawesh A. et al.Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo.J Clin Endocrinol Metab. 1997; 82: 4196-4200Crossref PubMed Google Scholar and skeletal muscle9.Febbraio M.A. Pedersen B.K. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles.FASEB J. 2002; 16: 1335-1347Crossref PubMed Scopus (617) Google Scholar are also a possible source of this cytokine. IL-6 mRNA is expressed in resting human muscle and is rapidly increased by contraction.9.Febbraio M.A. Pedersen B.K. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles.FASEB J. 2002; 16: 1335-1347Crossref PubMed Scopus (617) Google Scholar A release of IL-6 from the legs (which are mainly composed of skeletal muscle) has been shown to take place during physical exercise or glycogen depletion.9.Febbraio M.A. Pedersen B.K. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles.FASEB J. 2002; 16: 1335-1347Crossref PubMed Scopus (617) Google Scholar, 10.Febbraio M.A. Hiscock N. Sacchetti M. et al.Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction.Diabetes. 2004; 53: 1643-1648Crossref PubMed Scopus (283) Google Scholar In addition, it has been recently observed that insulin increases IL-6 gene expression in insulin-resistant, but not in healthy skeletal muscle11.Carey A.L. Lamont B. Andrikopoulos S. et al.Interleukin-6 gene expression is increased in insulin-resistant rat skeletal muscle following insulin stimulation.Biochem Biophys Res Commun. 2003; 302: 837-840Crossref PubMed Scopus (19) Google Scholar and that IL-6 is released by the forearm muscle in obese subjects.12.Corpeleijn E. Saris W.H.M. Jansen E.H.J.M. et al.Postprandial interleukin-6 release from skeletal muscle in men with impaired glucose tolerance can be reduced by weight loss.J Clin Endocrinol Metab. 2005; 90: 5819-5824Crossref PubMed Scopus (36) Google Scholar Both reactive oxygen species9.Febbraio M.A. Pedersen B.K. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles.FASEB J. 2002; 16: 1335-1347Crossref PubMed Scopus (617) Google Scholar, 10.Febbraio M.A. Hiscock N. Sacchetti M. et al.Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction.Diabetes. 2004; 53: 1643-1648Crossref PubMed Scopus (283) Google Scholar and lipopolysaccharide9.Febbraio M.A. Pedersen B.K. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles.FASEB J. 2002; 16: 1335-1347Crossref PubMed Scopus (617) Google Scholar, 10.Febbraio M.A. Hiscock N. Sacchetti M. et al.Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction.Diabetes. 2004; 53: 1643-1648Crossref PubMed Scopus (283) Google Scholar can upregulate muscle IL-6, likely because of an activation of nuclear factor, nuclear factor-κB. Muscle-derived IL-6 could play a physiological role to maintain metabolic homeostasis by stimulating lipolysis during periods of increased metabolic demand. In addition, in the context of skeletal muscle, IL-6 has variously been reported to regulate carbohydrate metabolism, increase satellite cell proliferation, or cause muscle wasting.11.Carey A.L. Lamont B. Andrikopoulos S. et al.Interleukin-6 gene expression is increased in insulin-resistant rat skeletal muscle following insulin stimulation.Biochem Biophys Res Commun. 2003; 302: 837-840Crossref PubMed Scopus (19) Google Scholar, 12.Corpeleijn E. Saris W.H.M. Jansen E.H.J.M. et al.Postprandial interleukin-6 release from skeletal muscle in men with impaired glucose tolerance can be reduced by weight loss.J Clin Endocrinol Metab. 2005; 90: 5819-5824Crossref PubMed Scopus (36) Google Scholar, 13.Haddad F. Zaldivar F.P. Cooper D.M. et al.IL-6 induced skeletal muscle atrophy.J Appl Physiol. 2005; 98: 911-917Crossref PubMed Scopus (358) Google Scholar, 14.Lang C.H. Silvis C. Deshpande N. et al.Endotoxin stimulates in vivo expression of inflammatory cytokines tumor necrosis factor alpha, interleukin-1beta, -6, and high-mobility-group protein-1 in skeletal muscle.Shock. 2003; 19: 538-546Crossref PubMed Scopus (157) Google Scholar Therefore, available data indicate that several physiologic and pathological stimuli are able to prime the mechanisms for muscle IL-6 release. Whether uremia induces changes in muscle IL-6 metabolism has never been examined. The aim of the present study was to explore the hypothesis that IL-6 could be locally produced in skeletal muscle and exported to other tissues. First, we studied the exchange of this cytokine across the forearm (which is mainly made of skeletal muscle) in patients with chronic kidney disease (CKD) (stages 3 and 4) and in hemodialysis (HD) patients. In addition, in order to further explore whether muscle cells per se are the source of the elevation in IL-6, we performed an analysis of both IL-6 protein (by immunohistochemistry) and IL-6 mRNA expressions in muscles of patients with severe chronic renal failure showing evidence of inflammation. Plasma flow across the forearm was 1.9±0.13, 2.2±0.15, and 2.2±0.30 ml/min/100 ml, respectively, in CKD, ESRD patients, and control subjects (P=NS). Individual arterial and venous levels of IL-6, as well as their exchange rates across the forearm are reported in Table 1. Arterial levels of IL-6 in controls were within the range of those previously reported in arterial plasma.15.Pantsulaia I. Trofimov S. Kobyliansky E. et al.Genetic and environmental influences on IL-6 and TNF-alpha plasma levels in apparently healthy general population.Cytokine. 2002; 19: 138-146Crossref PubMed Scopus (53) Google Scholar In addition, IL-6 levels in the deep forearm vein, although tendentiously higher, were not statistically different from their corresponding arterial level. Similar findings have been obtained across the forearm8.Mohamed-Alì V. Goodrick S. Rawesh A. et al.Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo.J Clin Endocrinol Metab. 1997; 82: 4196-4200Crossref PubMed Google Scholar and the leg12.Corpeleijn E. Saris W.H.M. Jansen E.H.J.M. et al.Postprandial interleukin-6 release from skeletal muscle in men with impaired glucose tolerance can be reduced by weight loss.J Clin Endocrinol Metab. 2005; 90: 5819-5824Crossref PubMed Scopus (36) Google Scholar in healthy subjects.Table 1Forearm exchange of interleukin-6 in patients in controlsArtery (pg/ml)Forearm vein (pg/ml)A-V differenceRate (pg/min 100 ml)Controls (n=6)3.2±0.983.5±0.99-0.2±0.20-0.5±0.4CKD (IL6 >5 pg/ml, n=7)28.8±6.2d,e,f29.6±6.26a-0.8±0.33-1.5±0.49CKD (IL6<5 pg/ml, n=9)2.5±0.482.8±0.54-0.3±0.25-0.9±0.45CKD (all subjects, n=16)14.0±4.2614.5±4.31a-0.5±0.17-1.12±0.28ESRD (IL6>5 pg/ml, n=10)44.1±7.36d,e49.6±8.54b-5.5±1.82-11.1±3.40d,hESRD (IL6<5 pg/ml, n=5)3.30±0.583.34±0.560±0.030±0.75ESRD (all subjects, n=15)30.5±7.05d34.4±8.08c-3.7±1.38-7.4±2.66gData are expressed as mean±s.e.m. Significance of difference of arterial (A) vs venous (V) concentration: aP<0.05, bP<0.035, cP<0.02.Significance of difference vs controls: dP<0.05 or less. Significance of difference vs the corresponding value in patients with low IL-6: eP<0.01. Significance of difference vs the corresponding value in ESRD patients with low IL-6: fP<0.001. Significance of difference vs the corresponding value in CKD (all subjects): gP<0.05. Significance of difference vs the corresponding value in CKD patients with high IL-6: hP<0.05.CKD, chronic kidney disease; ESRD, end-stage renal disease; IL-6, interleukin-6. Open table in a new tab Data are expressed as mean±s.e.m. Significance of difference of arterial (A) vs venous (V) concentration: aP<0.05, bP<0.035, cP<0.02. Significance of difference vs controls: dP<0.05 or less. Significance of difference vs the corresponding value in patients with low IL-6: eP<0.01. Significance of difference vs the corresponding value in ESRD patients with low IL-6: fP<0.001. Significance of difference vs the corresponding value in CKD (all subjects): gP<0.05. Significance of difference vs the corresponding value in CKD patients with high IL-6: hP<0.05.CKD, chronic kidney disease; ESRD, end-stage renal disease; IL-6, interleukin-6. Arterial IL-6 levels were >5 pg/ml in seven CKD and 10 ESRD patients. In these patients, the deep venous IL-6 levels were significantly higher than the corresponding value in the artery (Table 2). A release from peripheral tissues was observed only as a trend in CKD patients who showed IL-6 levels <5 pg/ml. When considered as a whole group, the negative arterio-venous difference for IL-6 was statistically significant (P<0.008) in CKD and ESRD patients. The release of IL-6 from peripheral tissues was about sevenfold increased in HD patients with high IL-6 vs the corresponding value in CKD patients. Arterial IL-6 was directly related to peripheral release of IL-6 in HD patients (r=0.69; P<0.004) (Figure 1a), suggesting that release from periphery can influence plasma IL-6 levels. However, this association was not statistically significant in CKD patients (r=0.331; P=NS) (Figure 1b).Table 2Characteristics of the patientsForearm balance study (CKD patients)Forearm balance study (HD patients)Muscle biopsy study (CKD patients)Gender (M/F)13M/3F12M/3F7M/8FAge (years)66±267±369±3Body weight (kg)73±468±467±4Height (cm)169±3168±3163±2BMI (kg/m2)26±124±125±1Fat-free mass (kg)49±246± 845±2Fat mass (kg)25±221±222±3nPNA (g/kg)0.90±0.11±0.10.85±0.1Estimated GFR (ml/min.1.73 m2)24±22±1b,c8.4±1bSerum creatinine (mg/dl)3.0±0.210±1b,c6.8±0.4bSerum albumin (g/dl)3.5±0.033.4±0.133.5±0.2BUN (mg/dl)61±584±8a84±3 aBicarbonate (mmol/l)23.1±0.5022.0±0.9023.2±0.9CRP (mg/l)12±335±8a28±8Hemoglobin (g/dl)12±110.5±111.3±0.3Cardiovascular scored2.08±0.232.94±0.352.13±0.46BMI, body mass index; BUN, blood urea nitrogen; CKD, chronic kidney disease; CRP, C-reactive protein; F, Female; HD, hemodialysis; M, male; nPNA, normalized protein nitrogen appearance; GFR, glomerular filtration rate. Significance of difference vs the forearm balance study: aP<0.05; bP<0.001. Data are expressed as mean±s.e.m. Significance of difference vs the muscle biopsy study: cP<0.05. Cardiovascular score was obtained by the use of a standardized four-level scale based on atherosclerotic events.25.Cheung A.K. Sarnak M.J. Yan G. et al.Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients.Kidney Int. 2000; 58: 353-362Abstract Full Text Full Text PDF PubMed Scopus (630) Google Scholar Open table in a new tab BMI, body mass index; BUN, blood urea nitrogen; CKD, chronic kidney disease; CRP, C-reactive protein; F, Female; HD, hemodialysis; M, male; nPNA, normalized protein nitrogen appearance; GFR, glomerular filtration rate. Significance of difference vs the forearm balance study: aP<0.05; bP<0.001. Data are expressed as mean±s.e.m. Significance of difference vs the muscle biopsy study: cP<0.05. Cardiovascular score was obtained by the use of a standardized four-level scale based on atherosclerotic events.25.Cheung A.K. Sarnak M.J. Yan G. et al.Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients.Kidney Int. 2000; 58: 353-362Abstract Full Text Full Text PDF PubMed Scopus (630) Google Scholar Cytokine arterial plasma levels were greater in patients with CKD than in controls (IL-1β=6.5±1.9, IL-10=2.7±0.2, and tumor necrosis factor-α=33.0±3.2 pg/ml in patients vs IL-1β=3.0±1, IL-10=1.7±0.2, and tumor necrosis factor-α=11.5±2 pg/ml in controls, P<0.05–0.01). Plasma levels of these cytokines tended to be further increased in HD patients (IL-1β=9.3±2.0, IL-10=5.8±0.3, and tumor necrosis factor-α=93±12 pg/ml, P<0.05-0.01 vs controls). However, no significant arterio-venous gradient across the forearm was observed for these cytokines both in control subjects and each patient category (data not reported). The evaluation of cardiovascular profile yielded a cardiovascular score higher in inflamed vs non-inflamed HD patients (3.78±0.32 vs 2±0.6, P<0.02). Conversely, this score was similar in inflamed vs non-inflamed CKD subjects (2.0±0.32 vs 2.0±0.29). The release of IL-6 from the forearm was linearly, directly related to the cardiovascular score in HD (r=0.603; P<0.003), but not in CKD patients (r=0.08; P=NS). C-reactive protein (CRP) levels correlated directly with forearm release of IL-6 (r=0.72; P<0.001). However, when patients were considered separately, this association persisted to be statistically significant in HD patients only (HD patients r=0.70, P<0.002; CKD patients, r=0.24, P=NS). No relationship was observed between indexes of obesity (body mass index and body fat mass), plasma bicarbonate, hemoglobin, uric acid, residual renal function, and the release of IL-6 from the forearm. Both in patients and controls, the deep venous phenylalanine levels exceeded the arterial ones (P<0.01), thus indicating phenylalanine release from the forearm and proteolysis. Net phenylalanine balance across the forearm in CKD and in dialyzed ESRD patients was similar to controls (Figure 2). When considering CKD patients separately according to IL-6 levels, net protein balance was also not different in patients with high vs low plasma IL-6. However, net phenylalanine balance was significantly more negative (indicating a decrease in muscle protein synthesis or an increase in protein degradation) in HD patients showing evidence of microinflammation as compared to non-inflamed HD subjects. Net phenylalanine balance was weakly related to IL-6 release from the forearm when considering together CKD and ESRD patients (r=0.365; P<0.1). However, a significant relation between forearm phenylalanine and IL-6 release was again observed in HD but not in CKD patients (r=0.469, P<0.037) (Figure 3a and b).Figure 3Relationship between the release of phenylalanine and that of IL-6 from peripheral tissues (a) in HD-treated patients with ESRD and (b) in patients with CKD (stages 3 and 4). The release of phenylalanine by peripheral tissues increased progressively along with the release of IL-6. This correlation was observed in HD, but not in CKD patients.View Large Image Figure ViewerDownload (PPT) Patients studied in this group displayed evidence of an inflammatory response (plasma CRP 28±5 mg/dl; IL-6 15±2 pg/ml). As Figure 4 shows, we were able to detect IL-6 mRNA in muscles, both in patients and in controls. Muscle IL-6 mRNA was, however, 2.4-fold increased (P<0.05) in patients vs controls. The IL-6 staining was absent in muscle tissue from healthy subjects. Representative images are shown (Figure 5a and b) for one control subject and three CKD patients. In CKD patients, the expression of IL-6 was clearly detectable (Figures 5 and 6). The IL-6 staining appeared as a diffuse staining of the cytoplasm of skeletal muscle fibers in all subjects. There was no IL-6 staining present between muscle fibers. In addition, mononuclear infiltrates were negative for IL-6 immunostaining.Figure 6Results of IL-6 image analysis (immunostaining) in patients with CKD (n=10) and controls (n=6) in the resting state. Values are means±s.e.m. *Significantly different (P<0.05) vs controls.View Large Image Figure ViewerDownload (PPT) In the present study, we tested the hypothesis that IL-6, a major mediator of the acute-phase response, is released by skeletal muscle both in patients with moderate advanced CKD and those with ESRD displaying evidence of an inflammatory response. This issue has been assessed by multiple determinations, including the measure of IL-6 balance across the forearm (which is mainly made of skeletal muscle), immunohistochemical evaluation of IL-6 in muscle, and muscle detection of IL-6 mRNA. First, we observed that IL-6 is released by peripheral tissues into the systemic circulation in patients with evidence of inflammation. On the contrary, no significant gradient of IL-6 occurs across peripheral tissues both in healthy controls and patients without evidence of an inflammatory response. In addition, we observed that IL-6 gene and protein expression are upregulated in skeletal muscle of patients with advanced CKD displaying an inflammatory response. Accordingly, the peripheral output of IL-6 in uremia can be attributed to an increase in IL-6 gene transcription within skeletal muscle and translation of IL-6 protein that is subsequently released. Our IL-6 tissue immunohistochemical findings in uremic patients are similar to those reported by Febbraio et al.,9.Febbraio M.A. Pedersen B.K. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles.FASEB J. 2002; 16: 1335-1347Crossref PubMed Scopus (617) Google Scholar who showed that IL-6 protein was distributed homogenously across muscle fibers in exercising healthy subjects. In our study, although only scanty mononuclear infiltrates were observed across muscle fibers in CKD patients, these were negative for IL-6 immunostaining (Figure 5). These considerations suggest that IL-6 is directly produced by muscle cells. Recently, it has been estimated that 10–35% of the body's basal circulating IL-6 is derived from adipose tissue.16.Fried S.K. Bunkin D.A. Greenberg A.S. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.J Clin Endocrinol Metab. 1998; 83: 847-855Crossref PubMed Scopus (1369) Google Scholar According to our data, the output of IL-6 from peripheral tissues can play a major role in influencing circulating levels of this cytokine in patients with CKD. Results obtained in healthy subjects that no significant enrichment or depletion of IL-6 occurs across the forearm muscle are in accordance with previous findings obtained across the forearm8.Mohamed-Alì V. Goodrick S. Rawesh A. et al.Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo.J Clin Endocrinol Metab. 1997; 82: 4196-4200Crossref PubMed Google Scholar and leg17.Steensberg A. Keller C. Starkie R.L. et al.IL-6 and TNF-alpha expression in, and release from, contracting human skeletal muscle.Am J Physiol Endocrinol Metab. 2002; 283: E1272-E1278Crossref PubMed Scopus (306) Google Scholar in the normal condition. The released IL-6 output from the forearm observed in CKD patients is of the same magnitude observed recently in obese, insulin-resistan subjects.12.Corpeleijn E. Saris W.H.M. Jansen E.H.J.M. et al.Postprandial interleukin-6 release from skeletal muscle in men with impaired glucose tolerance can be reduced by weight loss.J Clin Endocrinol Metab. 2005; 90: 5819-5824Crossref PubMed Scopus (36) Google Scholar According to the measure of the forearm arterio-venous gradient of IL-6 in obese subjects, the estimated contribution of IL-6 release from skeletal muscle to systemic IL-6 is about 12%, varying from 2 to 42%.12.Corpeleijn E. Saris W.H.M. Jansen E.H.J.M. et al.Postprandial interleukin-6 release from skeletal muscle in men with impaired glucose tolerance can be reduced by weight loss.J Clin Endocrinol Metab. 2005; 90: 5819-5824Crossref PubMed Scopus (36) Google Scholar In our study, we observed that the IL-6 output was fairly matched by variations in arterial levels of the same cytokine in HD, but not in CKD patients. The correlation coefficient of the relation is 0.69, indicating that about 48% of variations in arterial IL-6 were explained by variations in IL-6 release from periphery in HD subjects. According to the measurement errors in each variable, this indicates a strong association, and suggests that release by muscle plays a major role in determining IL-6 plasma levels in HD patients. The reason(s) why such an association was not found in patients with less-advanced renal disease may include on one hand, the residual metabolic activity of the kidney, which can remove IL-6 from blood (unpublished data from our laboratory), and, on the other hand, a more marked inflammatory condition in hemodialysis-treated patients. Which signals might trigger IL-6 release from muscle in uremia? Several upstream factors have been shown to be able to induce the transcription of this cytokine in human muscle in vitro or in vivo. IL-6 synthesis is activated by intracellular calcium levels, mitogen-activated protein kinases, and other cytokines such as IL-1β.9.Febbraio M.A. Pedersen B.K. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles.FASEB J. 2002; 16: 1335-1347Crossref PubMed Scopus (617) Google Scholar Nutritional factors, such as low glycogen availability, can also increase IL-6 transcription.17.Steensberg A. Keller C. Starkie R.L. et al.IL-6 and TNF-alpha expression in, and release from, contracting human skeletal muscle.Am J Physiol Endocrinol Metab. 2002; 283: E1272-E1278Crossref PubMed Scopus (306) Google Scholar Of note, the uptake of glucose by skeletal muscle is blunted18.Deferrari G. Robaudo C. Garibotto G. et al.Glucose interorgan exchange in chronic renal failure.Kidney Int. 1983; 24: S115-S122Google Scholar and muscle glycogen depletion have been reported by some studies in uremic patients. In addition, reactive oxygen species can upregulate muscle IL-6, likely because of an activation of nuclear factor, nuclear factor-κB.9.Febbraio M.A. Pedersen B.K. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles.FASEB J. 2002; 16: 1335-1347Crossref PubMed Scopus (617) Google Scholar, 10.Febbraio M.A. Hiscock N. Sacchetti M. et al.Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction.Diabetes. 2004; 53: 1643-1648Crossref PubMed Scopus (283) Google Scholar, 19.Chan M.H.S. McGee S.L. Watt M.J. et al.Altering dietary nutrient intake that reduces glycogen content leads to phosphorylation of nuclear p38 MAP kinase in human skeletal muscle: association with IL-6 gene transcription during contraction.FASEB J. 2004; 18: 1785-1787PubMed Google Scholar Another possible signal is related to metabolic acidosis. Metabolic acidosis contributes to the regulation of synthesis of inflammatory cytokines in circulating cells, and, possibly, in skeletal muscle.20.Bellocq A. Suberville S. Philippe C. et al.Low environmental pH is responsible for the induction of nitric-oxide synthase in macrophages. Evidence for involvement of nuclear factor-kappa B activation.J Biol Chem. 1998; 273: 5086-5092Crossref PubMed Scopus (175) Google Scholar, 21.Pickering W.P. Russ Price R. Bircher G. et al.Nutrition in CAPD: serum bicarbonate and the ubiquitin–proteasome system in muscle.Kidney Int. 2002; 61: 128692Abstract Full Text Full Text PDF Scopus (151) Google Scholar In this regard, we were not able to find a relation between bicarbonate levels and forearm release of IL-6. However, most of the patients in our study displayed bicarbonate levels in the normal range. We conclude that IL-6 expression is upregulated in muscle, and that forearm muscle releases substantial amounts of IL-6, a major mediator of the acute-phase response, in patients with CKD or ESRD and with evidence of inflammation. The relation between arterial IL-6 and CRP levels suggests that release of this cytokine from periphery may act as a signal for the inflammatory response. However, the biological effects of muscle-derived IL-6 in physiological and pathologic states are not completely ascertained. IL-6 released from muscle might behave as a hormone to increase substrate delivery.8.Mohamed-Alì V. Goodrick S. Rawesh A. et al.Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo.J Clin Endocrinol Metab. 1997; 82: 4196-4200Crossref PubMed Google Scholar One of the effects of IL-6 is to stimulate lipolysis, causing the release of NEFA from the adipocyte. This effect may be beneficial to sustain body needs during exercise, but could be harmful in chronic illness conditions.22.Axelsson J. Qureshi A.R. Suliman M.E. et al.Truncal fat mass as a contributor to inflammation in end-stage renal disease.Am J Clin Nutr. 2004; 80: 1222-1229PubMed Google Scholar In addition, IL-6 might beha" @default.
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• W2016451005 title "Peripheral tissue release of interleukin-6 in patients with chronic kidney diseases: Effects of end-stage renal disease and microinflammatory state" @default.
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