IL-6 protects pancreatic islet beta cells from pro-inflammatory cytokines-induced cell death and functional impairment in vitro and in vivo

Choi, Seung Eun; Choi, Kyung K.; Yoon, Ina; Shin, Jin Young; Kim, Jung-Sik; Park, Woong-Yang; Han, Duck Jong; Kim, Song Chul; Ahn, Curie; Kim, Jae Young; Hwang, Eung Soo; Chen, Yong; Szot, Gregory L.; Yoon, Kun Ho; Park, Chung Gyu

doi:10.1016/j.trim.2004.04.001

Cited by 119 publications

(103 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Consistent with these findings, the overexpression of CT-1 in the liver efficiently protects rats from fulminant hepatic failure after subtotal hepatectomy [8]. Furthermore, the CT-1-related cytokine IL-6 has been shown to act as a protective agent against apoptosis induced by pro-inflammatory cytokines in murine islets [9] while also impacting beta cell function indirectly through induction of glucagon-like peptide-1 (GLP-1) secretion from neighbouring alpha cells [10]. In this context, Il6-null mice showed altered carbohydrate and lipid metabolism as well as impairment in glucose homeostasis [11].…”

Section: Introductionsupporting

confidence: 55%

“…Data (mean ± SD) from three independent experiments were normalised to β-actin. *p< 0.05; **p<0.01 cytokines [9,23], while CT-1, a member of the IL-6 family of cytokines, has proven to be a survival factor for hepatocytes subjected to serum deprivation [7]. To analyse whether CT-1 also displayed cytoprotective effects on pancreatic beta cells, MIN6B1 cells were cultured for up to 120 h under serum deprivation conditions in the presence or absence of CT-1 (100 ng/ml).…”

Section: Resultsmentioning

confidence: 99%

“…CT-1 treatment induces expression of BCL-xL Since BCLxL has been demonstrated to be involved in IL-6-mediated suppression of apoptosis in murine islets [9], we analysed the levels of BCL-xL in MIN6B1 cells treated with CT-1 (100 ng/ml) by western blot. CT-1 treatment of freshly isolated islets subjected to 40 h of serum deprivation significantly increased BCL-xL content (Fig.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model

et al. 2013

View full text Add to dashboard Cite

Aims/hypothesis Cardiotrophin 1 (CT-1) is a recently described cytokine originally isolated from the heart where it has been shown to play an important role in apoptotic protection of cardiomyocytes and heart hypertrophy. Its beneficial properties have also been described in other organs such as liver and neuromuscular tissue. In the present study, we investigated whether CT-1 can confer protection against pro-apoptotic stimuli in pancreatic beta cells, and its role in insulin secretion and diabetes development.Methods The effects of CT-1 on apoptosis and function were studied using MIN6B1 cells and freshly isolated murine pancreatic islets. The impact on the development of diabetes was evaluated in Ct1-null (Ct1 −/− ) mice (the gene Ct1 is also known as Ctf1) using two streptozotocin (STZ)-induced models of diabetes. Results CT-1 has a protective effect in MIN6B1 cells and murine islets under the pro-apoptotic stimulus of serum deprivation, which correlates with the expression of B cell lymphoma-extra large, or following exposure to a mixture of cytokines. In addition, CT-1 enhances glucose-stimulated insulin secretion in MIN6B1 cells and this was repressed by inhibitors of phospholipase C. Furthermore, Ct1 −/− mice were more prone to develop diabetes, and their glucose tolerance test showed impaired plasma glucose clearance which correlated with decreased pancreatic insulin secretion. Conclusions/interpretation The results obtained from both in vitro and in vivo experiments show that CT-1 improves beta cell function and survival, and protects mice against STZ-induced diabetes.

show abstract

Section: Introductionsupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Analyses of the islets suggest that this was due to an increased cellular insulin content. Although the effect of IL-6 on insulin release has not been much studied, a few previous publications have found that IL-6 can increase insulin synthesis and secretion [43,44] and even protect the beta cells [45]. In contrast, it was recently reported that IL-6 reduced insulin secretion at low (3.3 mmol/l) but not at high (11.1 mmol/l) glucose concentrations in isolated islets from some animal models [46].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice

et al. 2008

View full text Add to dashboard Cite

Aims/hypothesis IL-6 is released by the adipose tissue and increased circulating levels in obesity are associated with hyperinsulinaemia and insulin resistance. Short-term experiments suggest that increased IL-6 release by the skeletal muscle following exercise may improve insulin sensitivity. Methods In order to examine the effect of chronically elevated IL-6 levels, we overexpressed Il6 in skeletal muscle in mice using an electro-transfer procedure.Results Circulating IL-6 levels were increased and the animals rapidly lost both weight and body fat, but food intake was unchanged, which is consistent with the finding that IL-6 increased energy expenditure. Insulin levels were inappropriately elevated and combined with hypoglycaemia in spite of reduced 2-deoxy-D-glucose uptake by skeletal muscle. Insulin-stimulated glucose uptake by skeletal muscles ex vivo was reduced, probably due to the decreased amounts of glucose transporter (GLUT)-4. Beta cell insulin content was increased, while apparent beta cell mass was unchanged. Circulating serum amyloid A cluster levels were increased tenfold due to a pronounced proinflammatory state in the liver with infiltration of inflammatory cells. However, no liver steatosis was found, which may be accounted for by concomitant AMP kinase activation. Conclusions/interpretation Chronically elevated IL-6 levels lead to inappropriate hyperinsulinaemia, reduced body weight, impaired insulin-stimulated glucose uptake by the skeletal muscles and marked inflammation in the liver. Thus, the pleiotrophic effects of chronically elevated IL-6 levels preclude any obvious usefulness in treating obesity or its associated metabolic complications in man, despite the fact that weight reduction may be expected.

show abstract

“…This panel is representative of three different experiments Further in-vitro experiments are needed to verify that α1-PI is really involved in protecting islet cells from the injury caused by cytokines, such as IL-1β, TNF-α and IFNγ [51]. In this regard, it is interesting to note that IL-6, a cytokine related to OSM, was shown to confer protection to pancreatic islet beta cells from cytokine-induced cell death [52]. It will also be important to assess the expression of α1-PI in islets of diabetic patients.…”

Section: Discussionmentioning

confidence: 98%

Expression and secretion of alpha1-proteinase inhibitor are regulated by proinflammatory cytokines in human pancreatic islet cells

et al. 2005

View full text Add to dashboard Cite

Aims/hypothesis: Alpha1-proteinase inhibitor (α1-PI) has been considered a key player in inflammatory processes. In humans, the main production site of α1-PI is the liver, but other tissues, including pancreatic islets, also synthesise this molecule. The aims of this study were to assess the islet cell types that produce α1-PI, to determine whether α1-PI is actually secreted by islet cells, and to assess how its production and/or secretion are regulated. Methods: Expression of α1-PI in human islet cells was assessed by immunofluorescence, electron microscopy and western blotting. Release of α1-PI was analysed by reverse haemolytic plaque assay and ELISA. The effects of cytokines on α1-PI synthesis and secretion were tested. Results: Immunofluorescence showed that alpha and delta cells do express α1-PI, whereas beta cells do not. By electron microscopy, we demonstrated a colocalisation of α1-PI with glucagon and somatostatin within secretory granules. Immunolabelling also revealed localisation of α1-PI within the Golgi apparatus, related vesicles and lysosomal structures. The expression of α1-PI in islet cells was also demonstrated by western blotting and ELISA of protein extracts. ELISA and reverse haemolytic plaque assay showed that α1-PI is secreted into the culture medium. Treatment of islet cells with IL-1β and oncostatin M for 4 days increased the production and release of α1-PI. Conclusions/interpretation: Our results demonstrate that α1-PI is expressed by the alpha and delta cells of human islets, and that proinflammatory cytokines enhance the production and release of this inhibitor.Keywords Human islets . IL-1β . Oncostatin M . α1-Proteinase inhibitor . Reverse haemolytic plaque assay Abbreviations OSM: oncostatin M . α1-PI: alpha1-proteinase inhibitor . RHPA: reverse haemolytic plaque assay

show abstract

IL-6 protects pancreatic islet beta cells from pro-inflammatory cytokines-induced cell death and functional impairment in vitro and in vivo

Cited by 119 publications

References 37 publications

Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model

Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model

Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice

Expression and secretion of alpha1-proteinase inhibitor are regulated by proinflammatory cytokines in human pancreatic islet cells

Contact Info

Product

Resources

About