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)

A plethora of myeloma growth factors (MGFs) has been identified, but their relative importance and cooperation have not been determined. We investigated 5 MGFs (interleukin-6 [IL-6], insulin-like growth factor type 1 [IGF-1], hepatocyte growth factor [HGF], HB-epidermal growth factor [HB-EGF], and a proliferation-inducing ligand [APRIL]) in serum-free cultures of human myeloma cell lines (HMCLs). In CD45(-) HMCLs, an autocrine IGF-1 loop promoted autonomous survival whereas CD45(+) HMCLs could not survive without addition of MGFs, mainly IGF-1 and IL-6. IGF-1 was the major one: its activity was abrogated by an IGF-1R inhibitor only, whereas IL-6, HGF, or HB-EGF activity was inhibited by both IGF-1R- and receptor-specific inhibition. APRIL activity was inhibited by its specific inhibitor only. Of the investigated MGFs and their receptors, only expressions of IGF-1R and IL-6R in multiple myeloma cells (MMCs) of patients delineate a group with adverse prognosis. This is mainly explained by a strong association of IGF-1R and IL-6R expression and t(4;14) translocation, but IGF-1R expression without t(4;14) can also have a poor prognosis. Thus, IGF-1-targeted therapy, eventually in combination with anti-IL-6 therapy, could be promising in a subset of patients with MMCs expressing IGF-1R.
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PMID:The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor. 1922 10

Our previous study demonstrated mRNA and protein expression of peroxisome proliferator-activated receptor-g (PPAR-g) in the immune system of weaned pigs. In this report, to test the hypothesis that activation of PPAR-g in immune system modulates inflammatory response, and adrenal and somatotropic responses associated with immune challenge, we administered intraperitoneally PPAR-g agonist and/or antagonist in weaned pigs subjected to Escherichia coli lipopolysaccharide (LPS) challenge. Unexpectedly, we found that a single injection of the PPAR-g agonist rosiglitazone (given at 3 mg/kg body weight 30 min before LPS injection) failed to block pro-inflammatory cytokine production induced by LPS injection. Rather, plasma levels of tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6), mRNA abundance of TNF-a in thymus, spleen, mesenteric lymph node and peripheral white blood cells, mRNA abundance of IL-6 in thymus, protein levels of TNF-a in spleen and mesenteric lymph node, and protein levels of IL-6 in spleen and mesenteric lymph node, were elevated beyond the levels in control pigs injected with LPS. Furthermore, rosiglitazone potentiated the increase of plasma cortisol and prostaglandin E(2) concentrations, and the decrease of plasma insulin-like growth factor-1 concentration induced by LPS injection. Co-administration of the PPAR-g antagonist bisphenol A diglycidyl ether (given 30 mg/kg body weight) 30 min prior to treatment with rosiglitazone antagonized the effect of the PPAR-g agonist, indicating a PPAR-g-dependent effect. Our data indicate that ligand-induced activation of PPAR-g does not ameliorate but enhances pro-inflammatory cytokine production, and further potentiates the adrenal and somatotropic changes in weaned pigs subjected to E. coli LPS challenge, which suggests that PPAR-g activation may not be useful, but potentially harmful, in the treatment of immune challenge in livestock. Our results raise doubts about the prevalently accepted anti-inflammatory role for PPAR-g activation.
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PMID:Activation of peroxisome proliferator-activated receptor-gamma potentiates pro-inflammatory cytokine production, and adrenal and somatotropic changes of weaned pigs after Escherichia coli lipopolysaccharide challenge. 1947 10

The phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway mediates proliferation, survival, and drug resistance in multiple myeloma (MM) cells. Here, we tested the anti-MM activity of NVP-BEZ235 (BEZ235), which inhibits PI3K/Akt/mTOR signaling at the levels of PI3K and mTOR. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric survival assays showed that MM cell lines exhibited dose- and time-dependent decreased viability after exposure to BEZ235 (IC(50), 25-800 nmol/L for 48 hours). MM cells highly sensitive (IC(50), <25 nmol/L) to BEZ235 (e.g., MM.1S, MM.1R, Dox40, and KMS-12-PE) included both lines sensitive and resistant to conventional (dexamethasone, cytotoxic chemotherapeutics) agents. Pharmacologically relevant BEZ235 concentrations (25-400 nmol/L) induced rapid commitment to and induction of MM.1S and OPM-2 cell death. Furthermore, normal donor peripheral blood mononuclear cells were less sensitive (IC(50), >800 nmol/L) than the majority of MM cell lines tested, suggesting a favorable therapeutic index. In addition, BEZ235 was able to target MM cells in the presence of exogenous interleukin-6, insulin-like growth factor-1, stromal cells, or osteoclasts, which are known to protect against various anti-MM agents. Molecular profiling revealed that BEZ235 treatment decreased the amplitude of transcriptional signatures previously associated with myc, ribosome, and proteasome function, as well as high-risk MM and undifferentiated human embryonic stem cells. In vivo xenograft studies revealed significant reduction in tumor burden (P = 0.011) and survival (P = 0.028) in BEZ235-treated human MM tumor-bearing mice. Combinations of BEZ235 with conventional (e.g., dexamethasone and doxorubicin) or novel (e.g., bortezomib) anti-MM agents showed lack of antagonism. These results indicate that BEZ235 merits clinical testing, alone and in combination with other agents, in MM.
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PMID:Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. 1958 92

The effect of a single exercise as well as exercise training on the growth hormone (GH)-insulin-like growth factor (IGF-I) axis and inflammatory cytokines was studied mainly in adults participating in individualized endurance-type sports. The gender-specific effect of exercise on these systems in adolescents is unknown. Therefore, the purpose of this study was to evaluate the effect of a typical volleyball practice on anabolic (GH, IGF-I, and testosterone) and catabolic hormones (cortisol) and inflammatory mediators (interleukin-6 [IL-6]) in elite, national team level, male (n = 14) and female (n = 13) adolescent volleyball players (13-18 years, Tanner stage 4-5). Exercise consisted of a typical 1-hour volleyball practice. Blood samples were collected before and immediately after the practice. Exercise led to significant increases in GH (0.2 +/- 0.1 to 2.7 +/- 0.7 and 1.7 +/- 0.5 to 6.4 +/- 1.4 ng x mL, in men and women, respectively, p < 0.05 for both), testosterone (6.1 +/- 0.9 to 7.3 +/- 1.0 and 2.4 +/- 0.6 to 3.3 +/- 0.7 ng x mL, in men and women, respectively, p < 0.05 for both), and IL-6 (1.1 +/- 0.6 to 3.1 +/- 1.5 and 1.2 +/- 0.5 to 2.5 +/- 1.1 pg x mL, in men and women, respectively, p < 0.002 for both). Exercise had no significant effect on IGF-I, insulin-like growth factor binding protein-3, and cortisol levels. There were no gender differences in the hormonal response to training. Changes in GH and testosterone after the volleyball practice suggest exercise-related anabolic adaptations. The increase in IL-6 may indicate its important role in muscle tissue repair. These changes may serve as an objective quantitative tool to monitor training intensity in unique occasions in team sports.
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PMID:The effect of a volleyball practice on anabolic hormones and inflammatory markers in elite male and female adolescent players. 1962 Sep 7

Deoxynivalenol (DON), a trichothecene mycotoxin found in grains and cereal-based foods worldwide, impairs weight gain in experimental animals but the underlying mechanisms remain undetermined. Oral exposure to DON induces rapid and transient upregulation of proinflammatory cytokine expression in the mouse. The latter are known to induce several suppressors of cytokine signaling (SOCS), some of which impair growth hormone (GH) signaling. We hypothesized that oral exposure to DON will induce SOCS expression in the mouse. Real-time PCR and cytokine bead array revealed that oral gavage with DON rapidly (1 h) induced tumor necrosis factor-alpha and interleukin-6 mRNA and protein expression in several organs and plasma, respectively. Upregulation of mRNAs for four well-characterized SOCS (CIS [cytokine-inducible SH2 domain protein], SOCS1, SOCS2, and SOCS3) was either concurrent with (1 h) or subsequent to cytokine upregulation (2 h). Notably, DON-induced SOCS3 mRNAs in muscle, spleen and liver, with CIS1, SOCS1, and SOCS2 occurring to a lesser extent. Hepatic SOCS3 mRNA was a very sensitive indicator of DON exposure with SOCS3 protein being detectable in the liver well after the onset of cytokine decline (5 h). Furthermore, hepatic SOCS upregulation was associated with about 75% suppression of GH-inducible insulin-like growth factor acid labile subunit. Taken together, DON-induced cytokine upregulation corresponded to increased expression of several SOCS, and was associated with suppression of GH-inducible gene expression in the liver.
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PMID:Induction of suppressors of cytokine signaling by the trichothecene deoxynivalenol in the mouse. 1993 2

Interleukin-6 (IL-6) is an important growth factor for myeloma cells. IL-6 promotes the survival and proliferation of multiple myeloma (MM) cells through the phosphorylated proteins, including STAT3, MAPK, and Akt. Chemical components that suppress the signaling proteins' phosphorylation have a potential role for MM therapy. We recently identified that baicalein, a component of Scutellaria radix, suppressed proliferation and induced apoptosis of myeloma cells by blocking IkappaB-alpha degradation followed by down-regulating IL-6 and XIAP gene expression. In the present study of four myeloma cell lines, namely U266, NOP2, AMO1, and ILKM2, we demonstrated that baicalein not only inhibited IL-6-mediated phosphorylation of signaling proteins, such as Jak, STAT3, MAPK, and Akt, but also inhibited the expression of their target genes, such as bcl-xl. Finally, baicalein facilitated myeloma cell proliferation inhibited by dexamethasone. In contrast, baicalin, another major flavonoid derived from Scutellaria radix, had no significant effect on IL-6-mediated protein phosphorylation. Baicalein had no effect on Akt phosphorylation induced by the insulin-like growth factor-1 (IGF-1) in NOP2 cells. Compared with PD98059, an MAPK inhibitor, baicalein exhibited a stronger inhibitory effect on Erk(1/2) phosphorylation. Our results demonstrate that baicalein is a potent inhibitor of protein phosphorylation induced by IL-6, and thus may be a useful agent for the treatment of MM.
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PMID:Inhibitory effect of baicalein on IL-6-mediated signaling cascades in human myeloma cells. 1987 71

The current study investigated the effects of a pre-cooling intervention on physiological and performance responses to team-sport training in the heat. Seven male lacrosse players performed a familiarization session and 2 randomized, counterbalanced sessions consisting of a 30-minute intermittent-sprint conditioning session. Prior to the sessions, players performed a 20-minute mixed-method, part-body cooling intervention (consisting of cooling vests, cold towels to the neck, and ice packs to the quadriceps) or no cooling intervention. Performance was determined from collection of 1 Hz global positioning system (GPS) data and analyzed for distance and speed. Prior to, during, and following the sessions, core temperature, heart rate, rating of perceived exertion (RPE), and thermal sensation scale (TSS) were measured; additionally, a venous blood sample was collected before and after each session for measurement of interleukin-6 (IL-6), insulin-like growth factor (IGF-1) and insulin-like growth factor-binding protein3 (IGF-BP3). Results indicated that a greater distance was covered during the pre-cooling condition (3.35 +/- 0.20 vs. 3.11 +/- 0.13 km; p = 0.05). Further, most of this improvement was evident from a greater distance covered during moderate intensities of 7 to 14 km/h (2.28 +/- 0.18 vs. 2.00 +/- 0.24 km; p = 0.05). Peak speeds and very-high-intensity efforts (20 km/h +/-) were not different between conditions (p > 0.05). The increase in core temperature was blunted following cooling, with a lower core temperature throughout the cooling session (38.8 +/- 0.3 vs. 39.3 +/- 0.4 degrees C; p < 0.05). However, there were no differences in heart rate, RPE, TSS, IL-6, IGF-1, or IGF-BP3 between conditions (p > 0.05). Accordingly, the use of a mixed-method, part-body cooling intervention prior to an intermittent-sprint training session in the heat can assist in reducing thermoregulatory load and improve aspects of training performance for team sports.
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PMID:The use of mixed-method, part-body pre-cooling procedures for team-sport athletes training in the heat. 1991 Aug 21

The aim of our study was to evaluate the neuroendocrine system in patients with juvenile idiopathic arthritis (JIA) regarding the activity of disease. Twenty-one JIA patients (mean age +/- standard deviation 10.5 +/- 4.1 years) were included. None of the patients was taking steroids or antitumor necrosis factor-alpha therapy during this study. Ten healthy volunteers and ten volunteers with upper respiratory tract infection composed the control groups. Furthermore, ten of the 21 JIA patients were also evaluated during the remission period. Erythrocyte sedimentation rate, C-reactive protein, adrenocorticotropic hormone (ACTH), cortisol, prolactin, insulin-like growth factor-1 (IGF-1), insulin-like growth factor-binding protein 3, free T3, free T4, thyroid-stimulating hormone, interleukin-6 (IL-6) levels, and 24-h urinary cortisol were evaluated both during the active period and remission. The median levels of ACTH and cortisol at 08:00 a.m. were significantly lower in patients with active JIA than patients in remission period and the control groups (p < 0.05). Furthermore, the median level of urine cortisol in active JIA patients was significantly lower than remission period and control groups (p < 0.05). The median level of IGF-1 was significantly lower in active patients than that of remission (p < 0.05). The median level of IL-6 in active JIA patients was significantly higher than those in remission and control groups (p < 0.05). Our preliminary study suggested that impaired secretion of adenohypophyseal hormones and distorted bilateral interactions between the immune and endocrine systems in JIA. Further studies are needed to clarify the consequences of the impaired hormone secretion in JIA.
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PMID:Low cortisol levels in active juvenile idiopathic arthritis. 2001 15

We demonstrated previously that administration of mesenchymal stromal cells (MSCs) after renal ischemia/reperfusion injury (IRI) in rats protected renal function and hastened repair through complex paracrine mechanisms. Here we investigated kidney-protective actions of MSCs in a porcine IRI model that may have relevance to human acute kidney injury (AKI). Groups of female pigs with bilateral IRI were infused with autologous or male allogeneic MSCs. No acute or late complications were observed, but unexpectedly, MSC therapy also had no beneficial effects on kidney function and histology. In vitro, we demonstrated substantial functional and phenotypic overlaps between rodent, human, and porcine MSCs, all of which exhibited trilineage differentiation, characteristic antigen profiles, and secretion of renoprotective vascular endothelial growth factor (VEGF)-A and insulin-like growth factor-1 (IGF-1). However, in striking contrast to human MSCs, porcine MSCs failed to inhibit the mixed lymphocyte reaction (MLR) and induced robust production of proinflammatory interleukin-6 (IL-6). In summary, in contrast to rodent models, treatment of porcine IRI with MSCs was not kidney-protective. This, we conclude, is due to the fact that porcine MSCs exert inadequate immune-modulating effects, further demonstrating that successful therapy of IRI with MSCs critically depends on their anti-inflammatory actions. As a consequence, treatment of AKI with MSCs is not informative regarding the investigation of the underlying mechanisms in this large animal model. We expect, however, that the treatment of human IRI of the kidney with immune-modulating MSCs will be as effective as in rodent models.
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PMID:Limited immune-modulating activity of porcine mesenchymal stromal cells abolishes their protective efficacy in acute kidney injury. 2014 56

Krabbe disease is an inherited lysosomal disorder in which galactosylsphingosine (psychosine) accumulates mainly in the central nervous system. To gain insight into the possible mechanism(s) that may be participating in the inhibition of the postnatal somatic growth described in the animal model of this disease (twitcher mouse, twi), we studied their femora. This study reports that twi femora are smaller than of those of wild type (wt), and present with abnormality of marrow cellularity, bone deposition (osteoblastic function), and osteoclastic activity. Furthermore, lipidomic analysis indicates altered sphingolipid homeostasis, but without significant changes in the levels of sphingolipid-derived intermediates of cell death (ceramide) or the levels of the osteoclast-osteoblast coupling factor (sphingosine-1-phosphate). However, there was significant accumulation of psychosine in the femora of adult twi animals as compared to wt, without induction of tumor necrosis factor-alpha or interleukin-6. Analysis of insulin-like growth factor-1 (IGF-1) plasma levels, a liver secreted hormone known to play a role in bone growth, indicated a drastic reduction in twi animals when compared to wt. To identify the cause of the decrease, we examined the IGF-1 mRNA expression and protein levels in the liver. The results indicated a significant reduction of IGF-1 mRNA as well as protein levels in the liver from twi as compared to wt littermates. Our data suggest that a combination of endogenous (psychosine) and endocrine (IGF-1) factors play a role in the inhibition of postnatal bone growth in twi mice; and further suggest that derangements of liver function may be contributing, at least in part, to this alteration.
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PMID:Factors that affect postnatal bone growth retardation in the twitcher murine model of Krabbe disease. 2044 93


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