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)

We present evidence that the survival of PC12 cells exposed to hydroxyl radicals generated by hydrogen peroxide applied for 30 min at 1 mM was effective when they were differentiated in response to Nerve Growth Factor (NGF) and/or other inducers of neurite outgrowth such as basic-fibroblast growth factor and dibutyryl cyclic AMP. The time- and dose-dependent differentiation triggered by NGF was (1) markedly increased by basic fibroblast growth factor, interleukin-6 or dibutyryl cyclic AMP; (2) diminished by leukemia inhibitory factor or ciliary neurotrophic factor; (3) not potentiated by insulin-like growth factor I or progesterone. The influence of these various factors and agents on PC12 cells was evaluated by the estimation of neurite outgrowth, whereas their possible protective effects were assessed by the measurement of cell survival. Our results would indicate that the factors and agents that induced differentiation were also able to protect the cells against an oxidative stress.
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PMID:Protective effect of neurotrophic factors, neuropoietic cytokines and dibutyryl cyclic AMP on hydrogen peroxide-induced cytotoxicity on PC12 cells: a possible link with the state of differentiation. 1009 19

Multiple myeloma (MM) is an invariably fatal disease that accounts for approximately 1% to 2% of all human cancers. Surprisingly little is known about the cellular pathways contributing to growth of these tumors. Although the cytokine interleukin-6 has been suggested to be the major stimulus for myeloma cell growth, the role of a second potential growth factor, insulin-like growth factor I (IGF-I), has been less clearly defined. The IGF-I signaling cascade in 8 MM cell lines was examined. In 7 of these, the IGF-I receptor (IGF-IR) was expressed and autophosphorylated in response to ligand. Downstream of IGF-IR, insulin receptor substrate 1 was phosphorylated, leading to the activation of phosphatidylinositol-3'-kinase (PI-3K). PI-3K, in turn, regulated 2 distinct pathways. The first included Akt and Bad, leading to an inhibition of apoptosis; the second included the mitogen-activated protein kinase (MAPK), resulting in proliferation. Biologic relevance of this pathway was demonstrated because in vitro IGF-I induced both an antiapoptotic and a proliferative effect. Importantly, in vivo administration of IGF-I in SCID mice inoculated with the OPM-2 line led to approximately twice the growth rate of tumor cells as in controls. These results suggest that IGF-I activates at least 2 pathways effecting myeloma cell growth and contributes significantly to expansion of these cells in vivo. (Blood. 2000;96:2856-2861)
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PMID:Insulin-like growth factor I is a dual effector of multiple myeloma cell growth. 1102 22

GH deficiency is associated with increased cardiovascular mortality and early manifestations of atherosclerosis. Elevated serum homocyst(e)ine levels have been found to be associated with increased cardiovascular risk. The effect of GH replacement on homocyst(e)ine has not been investigated to date. We evaluated the effect of GH replacement on fasting homocyst(e)inemia in a group of men with adult-onset GH deficiency in a randomized, single blind, placebo-controlled trial. Forty men with adult-onset GH deficiency were randomized to GH or placebo for 18 months, with dose adjustments made according to serum insulin-like growth factor I (IGF-I) levels. Fasting serum homocyst(e)ine, folate, vitamin B12, and total T(3) levels were determined at baseline and 6 and 18 months. Anthropometry, IGF-I levels, insulin, and glucose were measured at 1, 3, 6, 12, and 18 months. Nutritional assessment, body composition, total T(4), thyroid hormone binding index, and free T(4) index were assessed every 6 months. Homocyst(e)ine decreased in the GH-treated group compared with that in the placebo group (net difference, -1.2 +/- 0.6 micromol/L; confidence interval, -2.4, -0.02 micromol/L; P = 0.047). Homocyst(e)ine at baseline was negatively correlated with plasma levels of folate (r = -0.41; P = 0.0087). Total T(3) increased in the GH-treated group vs. that in the placebo group (net difference, 0.17 +/- 0.046 ng/dL; confidence interval, 0.071, 0.26 nmol/L; P = 0.0012). Folate and vitamin B12 levels did not significantly change between groups. Changes in homocyst(e)ine were negatively correlated with changes in IGF-I. For each 1 nmol/L increase in IGF-I, homocyst(e)ine decreased by 0.04 +/- 0.02 micromol/L (P = 0.029). In contrast, changes in homocyst(e)ine did not correlate with changes in folate, vitamin B12, total T(3), C-reactive protein, interleukin-6, or insulin levels. This study shows that GH replacement decreases fasting homocyst(e)ine levels compared with placebo. This may be one of the mechanisms involved in the putative modulation of atherosclerosis and cardiovascular risk by GH replacement.
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PMID:Effects of growth hormone (GH) administration on homocyst(e)ine levels in men with GH deficiency: a randomized controlled trial. 1129 77

Central hyposomatotropism and hypothyroidism have been inferred in long-stay intensive care patients. Pronounced hypoandrogenism presumably also contributes to the catabolic state of critical illness. Accordingly, the present study appraises the mechanism(s) of failure of the gonadotropic axis in prolonged critically ill men by assessing the effects of pulsatile GnRH treatment in this unique clinical context. To this end, 15 critically ill men (mean +/- SD age, 67 +/- 12 yr; intensive care unit stay, 25 +/- 9 days) participated, with baseline values compared with those of 50 age- and BMI-matched healthy men. Subjects were randomly allocated to 5 days of placebo or pulsatile iv GnRH administration (0.1 microg/kg every 90 min). LH, GH, and TSH secretion was quantified by deconvolution analysis of serum hormone concentration-time series obtained by sampling every 20 min from 2100-0600 h at baseline and on nights 1 and 5 of treatment. Serum concentrations of gonadal and adrenal steroids, T(4), T(3), insulin-like growth factor I (IGF), and IGF-binding proteins as well as circulating levels of cytokines and selected metabolic markers were measured. During prolonged critical illness, pulsatile LH secretion and mean LH concentrations (1.8 +/- 2.2 vs. 6.0 +/- 2.2 IU/L) were low in the face of extremely low circulating total testosterone (0.27 +/- 0.18 vs. 12.7 +/- 4.07 nmol/L; P < 0.0001) and relatively low estradiol (E(2); 58.3 +/- 51.9 vs. 85.7 +/- 18.6 pmol/L; P = 0.009) and sex hormone-binding globulin (39.1 +/- 11.7 vs. 48.6 +/- 27.8 nmol/L; P = 0.01). The molar ratio of E(2)/T was elevated 37-fold in ill men (P < 0.0001) and correlated negatively with the mean serum LH concentrations (r = -0.82; P = 0.0002). Pulsatile GH and TSH secretion were suppressed (P < or = 0.0004), as were mean serum IGF-I, IGF-binding protein-3, and acid-labile subunit concentrations; thyroid hormone levels; and dehydroepiandrosterone sulfate. Morning cortisol was within the normal range. Serum interleukin-1beta concentrations were normal, whereas interleukin-6 and tumor necrosis factor-alpha were elevated. Serum tumor necrosis factor-alpha was positively correlated with the molar E(2)/testosterone ratio and with type 1 procollagen; the latter was elevated, whereas osteocalcin was decreased. Ureagenesis and breakdown of bone were increased. C-Reactive protein and white blood cell counts were elevated; serum lactate levels were normal. Intermittent iv GnRH administration increased pulsatile LH secretion compared with placebo by an increment of +8.1 +/- 8.1 IU/L at 24 h (P = 0.001). This increase was only partially maintained after 5 days of treatment. GnRH pulses transiently increased serum testosterone by +174% on day 2 (P = 0.05), whereas all other endocrine parameters remained unaltered. GnRH tended to increase type 1 procollagen (P = 0.06), but did not change serum osteocalcin levels or bone breakdown. Ureagenesis was suppressed (P < 0.0001), and white blood cell count (P = 0.0001), C-reactive protein (P = 0.03), and lactate level (P = 0.01) were increased by GnRH compared with placebo infusions. In conclusion, hypogonadotropic hypogonadism in prolonged critically ill men is only partially overcome with exogenous iv GnRH pulses, pointing to combined hypothalamic-pituitary-gonadal origins of the profound hypoandrogenism evident in this context. In view of concomitant central hyposomatotropism and hypothyroidism, evaluating the effectiveness of pulsatile GnRH intervention together with GH and TSH secretagogues will be important.
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PMID:Five-day pulsatile gonadotropin-releasing hormone administration unveils combined hypothalamic-pituitary-gonadal defects underlying profound hypoandrogenism in men with prolonged critical illness. 1144 92

Expression of PTEN tumor suppressor gene has been known to dephosphorylate the phosphatidylinositol 3' kinase (PI3K) products on the 3 prime inositol ring, resulting in reduced Akt activation. Loss of PTEN expression in OPM2 and delta47 human myeloma lines led to high Akt activity toward insulin-like growth factor I (IGF-I). In contrast, mouse plasma cell tumor (PCT) lines, expressing wild type PTEN, did not respond to IGF-I for Akt activation. We demonstrated here that endogenous PTEN played a negative role in controlling Akt activity in both mouse PCT and NIH3T3 fibroblast lines by using anti-sense oligonucleotides against PTEN. To determine the role of src-homology 2-containing inositol 5' phosphatase (SHIP) in regulating the PI3K/Akt pathway, we manipulated its expression by down-regulation and overexpression in myeloma, PCT and NIH3T3 lines and analysed Akt activation. Our results showed that SHIP, unlike PTEN, did not affect Akt activity in all systems analysed, despite its ability to dephosphorylate a PI3K product. Although SHIP2 expression resulted in suppression of interleukin-6-mediated mitogen-activated protein kinase activation, expression of SHIP and SHIP2 in a PTEN-null myeloma line did not suppress Akt activity. Biologically, expression of only PTEN, but not SHIP and SHIP2, resulted in growth inhibition and increased apoptosis in OPM2 myeloma line. Together, our results have established the role of PTEN, but not SHIP and SHIP2, in negatively regulating the PI3K/Akt cascade and in myeloma leukemogenesis.
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PMID:PTEN, but not SHIP and SHIP2, suppresses the PI3K/Akt pathway and induces growth inhibition and apoptosis of myeloma cells. 1214 50

Deregulation of the inflammatory response plays a major role in the age-related decline of physical performance. The causal pathway leading from inflammation to disability has not been fully clarified, but several researches suggest that interleukin-6 (IL-6) causes a reduction of physical performance in elderly through its effect on muscle function. In vitro studies demonstrated that IL-6 inhibits the secretion of insulin-like growth factor I (IGF-I) and its biological activity, suggesting that the negative effect of IL-6 on muscle function might be mediated through IGF-I. We evaluated the joint effect of IGF-I and IL-6 on muscle function in a population-based sample of 526 persons with a wide age range (20-102 yr). After adjusting for potential confounders, such as age, sex, body mass index, IL-6 receptor, and IL-6 promoter polymorphism, IL-6, IGF-I, and their interaction were significant predictors of handgrip and muscle power. In analyses stratified by IL-6 tertiles, IGF-I was an independent predictor of muscle function only in subjects in the lowest IL-6 tertile, suggesting that the effect of IGF-I on muscle function depends on IL-6 levels. This mechanism may explain why IL-6 is a strong risk factor for disability.
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PMID:Chronic inflammation and the effect of IGF-I on muscle strength and power in older persons. 1241 77

Prostate cancer is one of the leading causes of death among men in the United States, and acquisition of hormone resistance (androgen independence) by cancer cells is a fatal event during the natural history of prostate cancer. Obesity is another serious health problem and has been shown to be associated with prostate cancer. However, little is known about the molecular basis of this association. Here we show that factor(s) secreted from adipocytes stimulate prostate cancer cell proliferation. Leptin is one of the major adipose cytokines, and it controls body weight homeostasis through food intake and energy expenditure. We identify leptin as a novel growth factor in androgen-independent prostate cancer cell growth. Strikingly, leptin stimulates cell proliferation specifically in androgen-independent DU145 and PC-3 prostate cancer cells but not in androgen-dependent LNCaP-FGC cells, although both cell types express functional leptin receptor isoforms. c-Jun NH2-terminal kinase (JNK) has been shown recently to play a crucial role in obesity and insulin resistance. Intriguingly, leptin induces JNK activation in androgen-independent prostate cancer cells, and the pharmacological inhibition of JNK blocked the leptin stimulation of androgen-independent prostate cancer cell proliferation. This suggests that JNK activation is required for leptin-mediated, androgen-independent prostate cancer cell proliferation. Furthermore, other cytokines produced by adipocytes and critical for body weight homeostasis cooperate with leptin in androgen-independent prostate cancer cell proliferation: interleukin-6 and insulin-like growth factor I demonstrate additive and synergistic effects on the leptin stimulation of androgen-independent prostate cancer cell proliferation, respectively. Therefore, adipose cytokines, as well as JNK, are key mediators between obesity and hormone-resistant prostate cancer and could be therapeutic targets.
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PMID:Prostate cancer cell-adipocyte interaction: leptin mediates androgen-independent prostate cancer cell proliferation through c-Jun NH2-terminal kinase. 1290 51

Amyloid precursor protein (AbetaPP), a precursor of amyloid beta (Abeta) peptide, is one of the molecules involved in the pathogenesis of Alzheimer's disease (AD). Specific mutations in AbetaPP have been found in patients inheriting familial AD (FAD). These mutant AbetaPP proteins cause cell death in neuronal cell lines in vitro, but the molecular mechanism of cytotoxicity has not yet been clarified completely. We analyzed the cytotoxic mechanisms of the London-type AbetaPP mutant, V642I-AbetaPP, in primary cortical neurons utilizing an adenovirus-mediated gene transfer system. Expression of V642I-AbetaPP protein induced degeneration of the primary neurons. This cytotoxicity was blocked by pertussis toxin, a specific inhibitor for heterotrimeric G proteins, Go/i, and was suppressed by an inhibitor of caspase-3/7 and an antioxidant, glutathione ethyl ester. A specific inhibitor for NADPH oxidase, apocynin, but not a xanthine oxidase inhibitor or a nitric oxide inhibitor, blocked V642I-AbetaPP-induced cytotoxicity. Among mitogen-activated protein kinase (MAPK) family proteins, c-Jun N-terminal kinase (JNK) and p38MAPK, but not extracellular regulated kinase (ERK), were involved in this cytotoxic pathway. The V642I-AbetaPP-induced cytotoxicity was not suppressed by two secretase inhibitors, suggesting that Abeta does not play a major role in this cytotoxicity. Two neuroprotective factors, insulin-like growth factor I (IGF-I) and Humanin, protected these primary neurons from V642I-AbetaPP-induced cytotoxicity. Furthermore, interleukin-6 and -11 also attenuated this cytotoxicity. This study demonstrated that the signaling pathway activated by mutated AbetaPP in the primary neurons is the same as that by the other artificial insults such as antibody binding to AbetaPP and the artificial dimerization of cytoplasmic domain of AbetaPP. The potential of neurotrophic factors and cytokines in AD therapy is also indicated.
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PMID:Characterization of V642I-AbetaPP-induced cytotoxicity in primary neurons. 1519 38

Selegiline inhibits the activity of monoamine oxidase B, enhances the release of dopamine, blocks the uptake of dopamine, acts as a calmodulin antagonist, and enhances the level of cyclic AMP, which in turn protects dopaminergic neurons. It possesses cognition-enhancing functions, rejuvenates serum insulin-like growth factor I in aged rats, and enhances life expectancy in rodents. Selegiline possesses neurotrophic-like actions, and rescues axotomized motorneurons independent of monoamine oxidase B inhibition. It enhances the synthesis of nerve growth factor, protects dopaminergic neurons from glutamate-mediated neurotoxicity, and protects dopaminergic neurons from toxic factors present in the spinal fluid of parkinsonian patients, and the said effect may be mediated via elaborating brain derived neurotrophic factor. Selegiline increases the striatal superoxide dismutase, protects against peroxynitrite- and nitric oxide-induced apoptosis, and guards dopaminergic neurons from toxicity induced by glutathione depletion. It stimulates the biosynthesis of interleukin 1-beta and interleukin-6, is an immunoenhancing substance, possesses antiapoptotic actions, and is neuroprotectant in nature. Selegiline has been shown to be efficacious in Parkinson's disease, global ischemia, Gille de la Tourette syndrome, and narcolepsy. Its therapeutic efficacy in Alzheimer's disease remains uncertain. In Alzheimer's disease, short term studies of selegiline suggest a beneficial effect; whereas long term studies are less convincing.
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PMID:Therapeutic efficacy of selegiline in neurodegenerative disorders and neurological diseases. 1710 May 91

The present study tests the hypotheses that local bioavailability of insulin-like growth factor I (IGF-I) is capable of regulating muscle protein balance and that muscle-directed IGF-I can selectively maintain muscle mass during bacterial infection. Initial studies in C57BL/6 mice demonstrated that increasing or decreasing bioavailable IGF-I within muscle by local administration of either Leu(24) Ala(31) IGF-I or IGF binding protein 1, respectively, produced proportional changes in surrogate markers (eg, phosphorylation of 4E-BP1 and S6K1) of protein synthesis. We next examined the ability of a sustained local administration of IGF-I to prevent sepsis-induced muscle atrophy over a 5-day period. At the time of cecal ligation and puncture or sham surgery, mice had a time-release pellet containing IGF-I implanted next to the gastrocnemius and a placebo pellet placed in the contralateral limb. Data indicated that IGF-I released locally only affected the adjacent muscle and was not released into the circulation. Gastrocnemius from septic mice containing the placebo pellet was atrophied and had a reduced IGF-I protein content. In contrast, locally directed IGF-I increased IGF-I protein within adjacent muscle to basal control levels. This change was associated with a proportional increase in muscle weight and protein, as well as increased phosphorylation of 4E-BP1 and the redistribution of eIF4E from the inactive eIF4E4EBP1 complex to the active eIF4EeIF4G complex. Local IGF-I also prevented the sepsis-induced increase in atrogin-1 messenger RNA in the exposed muscle. Finally, local IGF-I prevented the sepsis-induced increase in muscle interleukin-6 messenger RNA. Thus, muscle-directed IGF-I attenuates the sepsis-induced atrophic response apparently by increasing muscle protein synthesis and potentially decreasing proteolysis. Collectively, our data suggest that agents that increase the bioavailability of IGF-I within muscle per se might be effective in ameliorating the sepsis-induced loss of muscle mass without having undesirable effects on metabolic processes in distant organs.
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PMID:Local insulin-like growth factor I prevents sepsis-induced muscle atrophy. 1937 33


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