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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance contributes to a number of metabolic disorders, including type II diabetes, hypertension, and atherosclerosis. Cytokines, such as tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6, and hormones, such as growth hormone, are known to cause insulin resistance, but the mechanisms by which they inhibit the cellular response to insulin have not been elucidated. One mechanism by which these agents could cause insulin resistance is by inducing the expression of cellular proteins that inhibit insulin receptor (IR) signaling. Suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling pathways, the expression of which is regulated by certain cytokines. SOCS proteins are therefore attractive candidates as mediators of cytokine-induced insulin resistance. We have found that SOCS-1 and SOCS-6 interact with the IR when expressed in human hepatoma cells (HepG2) or in rat hepatoma cells overexpressing the human IR. In SOCS-1-expressing cells, insulin treatment increases the extent of interaction with the IR, whereas in SOCS-6-expressing cells the association with the IR appears to require insulin treatment. SOCS-1 and SOCS-6 do not inhibit insulin-dependent IR autophosphorylation, but both proteins inhibit insulin-dependent activation of ERK1/2 and protein kinase B in vivo and IR-directed phosphorylation of IRS-1 in vitro. These results suggest that SOCS proteins may be inhibitors of IR signaling and could mediate cytokine-induced insulin resistance and contribute to the pathogenesis of type II diabetes.
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PMID:Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistance. 1134 31

In 1994, Zhang et al. of Rockefeller University in New York reported the first successful complementary DNA (cDNA) cloning of leptin by the positional cloning method. Leptin was identified as the gene of ob/ob mouse in genetic obesity syndromes. It has very strong food intake control, and body weight and energy expenditure. The name "leptin" derived from the Greek word leptos, meaning "thin." We hereby review major advances leading to our current finding of leptin, leptin receptor and its structure, the outline of homozygote, and also influence of leptin in the pituitary. (The structure of leptin) The mouse obese gene has been localized to chromosome 6. With human leptin gene on chromosome 7q31.3, its DNA has more than 15000 base pairs and consists of three exons and two introns. For bioactivation of leptin the importance of disulfide-binding site is suggested. Human leptin which replaced the 128-th arginine with glutamine has the function of an aldosteron antagonist, which is reported to have the function of athrocytosis inhibition. The resemblance of leptin precursor of human, mouse and rat is very high, i.e., mouse and rat homology is 96% and mouse and human homology is 83%. (The structure of leptin receptor) The mutant gene, which is the cause of obesity, was shown on map on diabetic mouse (db/db) chromosome 4, and it was proven to be the same as the leptin receptor gene cloned by Tartaglia et all. Further studies have found the Zucker fatty rat (fa/fa) to be incorporated into a linkage map of rat chromosome 5, whose region of rat is the equivalent to the region of conserved synteny of the db/db mouse gene. The leptin receptor is glycoprotein consisting of a single transmembrane-spanning component. The primary structure of leptin receptor belongs to the cytokine-class1 family, the single membrane-spanning receptor, and is highly related to the gp130 signal-transducing component of the interleukin-6 (IL-6) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the leukemia inhibitory factor (LIF) receptor. The leptin receptor is known to have at least six existing isoforms (Ob-Ra, b, c, d, e, f) from the difference in splicing. (Homozygote Mutation of Leptin and Leptin Receptor :Hormone Secretion Disorders) The point mutation of ob/ob mouse and the splicing mutation of db/db mouse show remarkable obesity and hyperphagia. These obesity models show a reproduction disorder with both the male and the female, and they develop with homozygote. The cause is thought to be the gonadotropin secretory abnormality in pituitary. Three family lines report the cases of this deficiency, and it is considered that the secretory abnormality in pituitary develops into hypogonadotropic. These patients show low value in plasma FSHbeta (follicle stimulating hormone-beta and LHbeta (luteinizing hormone-beta which are produced from pituitary, and the plasma GnRH (gonadotropin releasing hormone) level is also low. Furthermore, the leptin receptor deficient family line was reported in 1998, in which case only the homozygote developed. The plasma leptin concentration of normal human is about 8.0 ng/ml, and this case with leptin receptor deficiency has high value of 500-700 ng/ml, which is the equivalent to the db/db mouse. (Role of Leptin in Hypothalamus-Pituitary-Periphery Function) The role of leptin which regulates pituitary hormones suggests the promotion the GHRH (growth hormone releasing hormone) secretion in hypothalamus-pituitary axis, with the possibility of the rise in secretion of GH (growth hormone) in pituitary, i.e. effects of icv (intracerebroventricular) infusion of leptin has spontaneously stimulated GHRH, which promotes GH secretion in the normal rats. On the other hand, topical treatment of GH3 (derived from a rat pituitary GH-secreting cell line) with leptin directly inhibits cell proliferation. The obesity model animals (ob/ob, db/db, fa/fa) have equally plump body compared to the normal models, which shows signs of sufficient growth. (Localization and Functional Relevance of Leptin and Leptin Receptor in Rodents Pituitary) Aside from being the food intake inhibitor and the energy control factor, leptin takes part in controlling the pituitary hormones. Promoting the secretion of GH, PRL (prolactin), TSHbeta (thyroid stimulating hormone-beta, FSHbeta/LHbeta, and inhibiting the secretion of ACTH (adrenocorticotropic hormone) are the major changes of pituitary hormones which are brought on by leptin. The expressive localization is specific, and immunohistochemistry (IHC) method recognized leptin in granular state in FSHbeta, LHbeta and TSHbeta positive cells. In our biochemical examination, the bulk of the expression of leptin is recognized in fraction of the secretory granule. In particular, FSHbeta cells had the highest percentage rate of colocalized leptin in rat pituitary. On the other hand, leptin receptor has been reported to be found only in normal rat pituitary, human pituitary adenoma, and respective cell lines in pituitaries by the RT-PCR method until now, but we disclosed for the first time the localization of leptin receptor on the plasma membrane of GH-secreting cells with the IHC method that has not been cleared so far. These findings show that leptin and leptin receptor have been expressed in different cells, and that the rat pituitary glands entertain paracrine mechanism between leptin (FSHbeta/LHbeta cells) and leptin receptor (GH cells). The function of paracrine in this pituitary suggests a new point of view in hypothalamus-pituitary axis, and it shall be concerned with many aspects such as hormone secretions and proliferation/inhibition. (Human Pituitary Adenoma) Preliminary report of leptin and leptin-receptor relationship with pituitary adenoma that has secretion abnormality has been filed, and its manifestation is being observed by the RT-PCR. Leptin and leptin receptor are expressed in most adenoma, and it is thought to function by autocrine and paracrine pathway in the adenomas. Leptin has been located in ACTH-secreting adenoma most frequently, especially in ACTH carcinoma. The leptin receptor is detected in all adenomas with high percentage rate, with both long and short forms, and then many cases of nonfunctioning pituitary adenomas, compared with other adenomas, have been reported to be positive with both long and short forms of leptin receptor as detected by RT-PCR. The HP75 cell line is derived from the nonfunctioning pituitary adenoma, which produces FSHbeta and LHbeta. The expression of leptin receptor in nonfunctioning pituitary adenoma, and the suppression of HP75 multiplication may lead to the possible hypothesis of leptin becoming one factor for the treatment of pituitary adenoma, especially in gonadotropin adenomas.
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PMID:Leptin and the pituitary. 1182 4

A new family of cytokine-inducible proteins, termed "suppressors of cytokine signaling" (SOCS), was discovered recently; these proteins function as negative regulators of signaling pathways involved in the cellular actions of many cytokines, growth factors, and hormones. Gene manipulation studies in mice point to the central importance of individual SOCS proteins in maintaining homeostasis by limiting cellular responses to specific cytokines or growth factors in a variety of different physiological systems. Cytokines modulate a wide variety of biological responses in the CNS, so members of the SOCS family might play crucial roles in regulating intracellular signaling by these effectors in both normal and disease states. Although to date studies of the neurobiology of the SOCS family have been limited, we know that many SOCS genes are constitutively expressed in the developing and adult brain, whereas the expression of others, particularly the SOCS1 and SOCS3 genes, can be highly regulated. Furthermore, roles for the SOCS are now evident in the modulation of neuroimmunoendocrine functions affected by a variety of cytokines, including leptin and members of the growth hormone and the interleukin-6/gp130 superfamilies. Overall, these findings point to the SOCS as likely crucial negative modulators in the temporal and spatial regulation and intensity of cytokine signaling and therefore actions in the CNS.
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PMID:Cytokine signaling in the brain: putting a SOCS in it? 1183 8

Here we report the cloning of a novel type I cytokine receptor, gp130-like monocyte receptor (GLM-R), with homology to the interleukin-6 receptor signal transducing chain, gp130, and granulocyte colony-stimulating factor receptor. Human and murine GLM-R cDNAs encode open reading frames of 732 and 716 amino acids, respectively, and the corresponding genes are located in close proximity to gp130 genes on human chromosome 5 and mouse chromosome 13. GLM-R is specifically expressed on CD14-positive cells and is up-regulated more than 50-fold upon activation of those cells. To address the question of whether GLM-R is a signaling receptor, we constructed a chimeric molecule, consisting of the extracellular domain of human growth hormone (hGH) receptor, and the intracellular domain of GLM-R. When transfected into factor-dependent 32D cells, this chimeric molecule could signal for proliferation and activate signal transducer and activator of transcription (STAT)-3 and STAT-5 upon stimulation with hGH. Thus, GLM-R is a novel signaling receptor chain potentially involved in the development and function of monocytes and macrophages.
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PMID:A novel type I cytokine receptor is expressed on monocytes, signals proliferation, and activates STAT-3 and STAT-5. 1187 49

The erosion of lean body mass resulting from protracted critical illness remains a significant risk factor for increased morbidity and mortality in this patient population. Previous studies have documented the well known impairment in nitrogen balance results from both an increase in muscle protein degradation as well as a decreased rate of both myofibrillar and sacroplasmic protein synthesis. This protein imbalance may be caused by an increased presence or activity of various catabolic agents, such as tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6 or glucocorticoids, or may be mediated via a decreased concentration or responsiveness to various anabolic hormones, such as growth hormone or insulin-like growth factor-I. This review focuses on recent developments pertaining to the importance of alterations in the growth hormone-insulin-like growth factor-I axis as a mechanism for the observed defects in muscle protein balance.
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PMID:Role of growth hormone, insulin-like growth factor-I, and insulin-like growth factor binding proteins in the catabolic response to injury and infection. 1195 52

We hypothesized that brief exercise of a small muscle group would lead to local rather than systemic alterations in cytokines, peripheral blood mononuclear cells, and mediators of angiogenesis. Fifteen men and eight women (age range 22-36 yr old) performed 10 min of unilateral wrist flexion exercise. Blood was sampled from venous catheters in the resting and exercising arm at baseline, at the end of exercise, and at 10, 30, 60, and 120 min after exercise. Lactate was significantly elevated in the exercising arm (+276 +/- 35%; P < 0.0005) with no change in the resting arm. In contrast, increases in both arms were observed for interleukin-6 (+139 +/- 51%; P < 0.0005), growth hormone (+1,104 +/- 284%; P < 0.003), natural killer cells (+81 +/- 9%; P < 0.0005), and lymphocytes expressing CD62L, CD11a, and CD54. There were no significant differences in these increases between the resting and exercising arm. Catecholamines increased in both arms [epinephrine peak increase, +226 +/- 36% (P < 0.001); norepinephrine peak increase, +90 +/- 15% (P < 0.01)]. Fibroblast growth factor-2 initially decreased with exercise in both arms, and this was followed by a rebound increase. Vascular endothelial growth factor demonstrated a small but significant increase in both arms (+124 +/- 31%; P < 0.05). Brief, low-intensity exercise leads to a systemic rather than local response of mediators that could be involved in inflammation, repair, or angiogenic adaptation to physical activity.
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PMID:Systemic vs. local cytokine and leukocyte responses to unilateral wrist flexion exercise. 1213 63

Growth failure is common in children with inflammatory bowel disease (IBD) and has been attributed chiefly to undernutrition. Liquid enteral feeding can reverse the calorie deficit and increase growth velocity. The inflammatory process per se may also directly inhibit linear growth. After institution of enteral nutrition, significant changes in serum growth factors and inflammatory indices have been observed before any changes in nutritional parameters [Bannerjee et al., Gastroenterology 2000;118:A526]. In rats with trinitrobenzenesulphonic acid (TNBS)-induced colitis, about 60% of the final growth impairment can be attributed to undernutrition, inflammation accounting for the remaining growth deficit. Young patients with Crohn's disease and growth failure have normal stimulated and spontaneous growth hormone (GH) secretion and reduced plasma concentrations of insulin-like growth factor-1 (IGF-I), suggesting a degree of GH resistance. Rats with TNBS colitis also have normal plasma GH and reduced IGF-I concentrations, mediated by a combination of undernutrition and active inflammation. Immunoneutralization of interleukin-6 (IL-6) increases hepatic IGF-I mRNA expression, plasma concentrations of IGF-I and linear growth. In contrast, administration of anti-tumour necrosis factor-alpha antibodies (TNF-ab) had no effect on IGF-I in this model. TNFab did, however, increase linear growth, suggesting inhibitory effects of TNF-alpha on the growth axis by mechanisms other than reduction in IGF-I. Preliminary data suggests that TNF-alpha inhibits maturation of growth plate chondrocytes. We have identified IL-6 receptors on growth plate chondrocytes but to date have not identified the effect, if any, of IL-6 directly at the growth plate.
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PMID:Fundamental mechanisms of growth failure in inflammatory bowel disease. 1237 6

The gp130-cytokine system has been fertile ground for protein structure-function studies aimed at elucidating the basis of ligand recognition and receptor activation. A number of longstanding questions involve the mechanism of the stepwise assembly of the active signaling complexes, as well as the structure of the gp130-cytokine complexes. It has been clear from functional studies that the paradigm of gp130-cyokine recognition will differ substantially from the classical homo-dimeric systems, typified by human growth hormone (hGH) and its receptor. Recently, a crystal structure of a viral interleukin-6 (vIL-6), complexed with the D1D2D3 domains of the gp130 extracellular domain, has resolved many of these questions, and reconciled much of the functional and mutagenesis data which have existed for a variety of gp130-cytokines. In this review, we discuss the structure of the vIL-6/gp130 complex in some detail and suggest that the geometry of this complex will be a common structural template utilized by other gp130-cytokines, as well as cytokines from distinct signaling systems.
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PMID:A structural template for gp130-cytokine signaling assemblies. 1242 68

This paper is concerned with growth retardation associated with overproduction of interleukin-6 (IL-6). As a model, we used MUP/hIL-6 transgenic mice in which human IL-6 cDNA is overexpressed under the control of a MUP gene enhancer/promoter. The growth-retardation of MUP/hIL-6 transgenic mice was paralleled by reduced serum levels of IGF-I. As shown, hepatic IGF-I mRNA levels were reduced in the transgenic mice. MUP/hIL-6 transgenic mice are in a state of growth hormone (GH)-resistance, since their serum GH levels are either normal or elevated. To identify possible steps in GH signaling which might be perturbed in the transgenic mice, we examined the synthesis of GH receptor (GHR) mRNA. We noted a twofold reduction of hepatic GHR mRNA in the transgenic mice. We therefore conclude that overexpression of IL-6 brings about growth impairment in part through a GH receptor defect.
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PMID:IL-6-overexpression brings about growth impairment potentially through a GH receptor defect. 1242 24

Satellite cells were isolated from biopsies of the biceps femoris of adult dogs. Virtually all cells expressed muscle-specific proteins. Proliferation of satellite cells increased as the concentration of fetal calf serum (FCS) was increased from 1 to 10% of the basal medium. The addition of mitogenic growth factors resulted in greater proliferation than that of cells cultured in basal medium alone. Maximum proliferation was obtained when fibroblast growth factor-basic (FGF2) was added to the medium, but differences existed between sources or types. Proliferation did not plateau when the concentration of recombinant human FGF2 was 75 ng/ml but reached maximum levels when 50 ng/ml of bovine FGF2 or 10 ng/ml of growth hormone or insulin-like growth factor-1 were added to the medium. Proliferation of satellite cells decreased when more than 5 ng/ml of transforming growth factor-alpha was included in the medium. Exposure of canine satellite cells to chemically defined media induced greater fusion of total nuclei (ODM-34%; 4F, ITT-CF, and SFG-23%) than exposure to other treatments, such as basal medium plus 2 mg/ml of 1-beta-d-arabinofuranosylcytosine, 5% chick embryo extract, 1% horse serum (average 9% fused nuclei), or 1% FCS (2% fused nuclei). Actin, myosin, desmin, neural cell adhesion molecule, MyoD1, and myogenin were expressed by canine satellite cells, but expression of major histocompatibility complex class II antigen was not detected. Reverse transcriptase-polymerase chain reaction detected expression of messenger ribonucleic acid for interleukin-6 (IL-6), IL-15, and leukemia inhibitory factor by canine satellite cells. Collectively, these data suggest that isolated canine satellite cells display properties of other types of myogenic cells and may be useful for further study of the regulation of postnatal myogenesis.
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PMID:Isolation and characterization of canine satellite cells. 1260 41


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