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)

It has been suggested that microgravity alters bone metabolism. Evidence for this phenomenon includes the negative calcium balance and decreased bone density in astronauts, as well as, inhibition of bone formation in rats flown for 2 to 3 weeks. However, the specific mechanisms that modulate these changes in microgravity are unknown. The purpose of this study was to clarify the mechanism of microgravity-induced bone demineralization using normal rat osteoblasts obtained from femur marrow cultures. The osteoblasts were cultured for 5 days during a Shuttle-Spacelab flight (STS-65). After collection of the culture medium, the cellular DNA and RNA were fixed on board. Enzyme-immunoassay of the culture medium for prostaglandin E2 (PGE2) indicated that microgravity induced a 4.5- to 136-fold increase in flight samples as compared to the ground control cultures. This increase of PGE2 production was consistent with a 3.3- to 9.5-fold elevation of inducible prostaglandin G/H synthase-2 (PGHS-2) mRNA, quantitated by reverse transcription-polymerase chain reaction (RT-PCR). The mRNA induction for the constitutive isozyme PGHS-1 was less than that for PGHS-2. The interleukin-6 (IL-6) mRNA was also increased (6.4- to 9.3-fold) in microgravity as compared to the ground controls. Since PGE2 and IL-6 are both known to play a role in osteoclast formation and bone resorption, these data provide molecular mechanisms that contribute to our understanding of microgravity-induced alterations in the bone resorption process.
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PMID:Microgravity induces prostaglandin E2 and interleukin-6 production in normal rat osteoblasts: role in bone demineralization. 898 71

Transglutaminase is a calcium-dependent enzyme that catalyzes an amine incorporation and a cross-linking of proteins. Intracellular transglutaminase is induced when human promyelocytic leukemia HL-60 cells are treated with retinoic acid and human hepatoblastoma HepG2 cells, with interleukin-6. To find whether the intracellular reaction catalyzed by transglutaminase increased when the enzyme is induced in these cells, the transglutaminase-catalyzed incorporation of 14C-labeled methylamine into cellular proteins was measured. The incorporation level of the labeled methylamine into proteins of HL-60 and HepG2 cells did not increase after the transglutaminase had been induced. The presence of the calcium ionophore A23187 did not affect these results. These findings suggested that even after the enzyme induction the catalytic action of intracellular transglutaminase is maintained at a constant level in these cells by unknown regulatory mechanism(s).
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PMID:Analysis of catalytic action of transglutaminase induced in human promyelocytic leukemia (HL-60) and human hepatoblastoma (HepG2) cells. 898 79

Interleukin-6 (IL-6) is known to enhance osteoclast recruitment, and thereby bone resorption. Thus, IL-6 has been proposed to mediate hypercalcemia in multiple myeloma and the enhanced osteoclastic activity seen in postmenopausal osteoporosis. We recently reported that the calcium concentration in plasma affects IL-6 secretion from mononuclear blood cells. To investigate the underlying mechanism, we have studied the effect of calcium on IL-6 formation in mononuclear blood cells ex vivo and in vitro. Thirteen healthy volunteers were given 1 g of calcium orally after overnight fasting. Plasma levels of ionized calcium (pCa2+) and serum levels of parathyroid hormone (sPTH) were measured after 2 and 4 h, with all subjects still fasting. After 2 h, pCa2+ was increased and sPTH decreased in all 13 persons. IL-6 secretion ex vivo from mononuclear blood cells drawn 4 h after calcium intake was increased 185% as compared with IL-6 secretion from cells drawn just before calcium intake. In control experiments without calcium intake, there was no alteration in pCa2+ and no effect on IL-6 secretion from mononuclear blood cells. In vitro studies revealed that stimulation of isolated mononuclear blood cells with physiological concentrations of calcium dose-dependently increased IL-6 secretion with an estimated EC50 at 1.2 mM Ca2+. No effect on the IL-6 secretion was seen following treatment of the isolated mononuclear blood cells with PTH or calcitonin. These observations demonstrate that the plasma calcium concentration affects IL-6 secretion from mononuclear blood cells. The in vitro data indicate the involvement of a direct calcium sensing mechanism. These findings might have implications in hypercalcemia and should also be borne in mind when considering the role of cytokines in osteoporosis.
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PMID:Regulation of interleukin-6 secretion from mononuclear blood cells by extracellular calcium. 904 Oct 54

Advanced glycation end-products (AGEs) are formed in long-lived matrix proteins by a non-enzymatic reaction with sugar. We recently demonstrated the presence of AGEs in amyloid fibrils of dialysis-related amyloidosis, one of the characteristic features of which is an accelerated bone resorption around amyloid deposits. This suggested a potential link of AGEs in bone resorption and led us to investigate whether AGEs enhance bone resorption. An immunohistochemical study using anti-AGE antibody revealed positive immunostaining for AGEs in bone tissues from elderly subjects. AGE-modified proteins were shown to stimulate monocyte/macrophage to secrete bone-resorbing cytokines such as interleukin-1 beta, interleukin-6 and tumour necrosis factor- alpha. AGE-modified proteins enhanced net calcium efflux in cultured neonatal mouse calvariae to a much greater extent than unmodified proteins. Furthermore, when mouse unfractionated bone cells containing osteoclasts were cultured on dentin slices, AGE-modified proteins increased the number of resorption pits formed by osteoclasts, whereas their normal counterparts or those modified with the early glycation products did not. These findings suggest that AGEs enhance bone resorption by osteoclasts. The modification of bone matrices with AGEs might, therefore, play a pathophysiological role not only in the remodelling of senescent bone matrix tissues, but also in dialysis-related amyloidosis or osteoporosis associated with diabetes and ageing.
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PMID:Possible involvement of advanced glycation end-products in bone resorption. 904 8

In order to identify possible correlations between interleukin-6 (IL-6) and hormonal and biochemical parameters of bone metabolism, or bone density, 24 postmenopausal women were studied. Serum IL-6, estradiol, calcium, phosphorus, osteocalcin, alkaline phosphatase, the urinary secretion of calcium, phosphorus and hydroxyproline, and bone density of the lumbar spine, femur and radius were measured. No significant correlation was found between IL-6 and the biochemical parameters. A negative correlation was found between IL-6 and serum estradiol, as well as between IL-6 and bone density in 5 out of 6 sites studied. It is possible that women with high IL-6 levels, may develop lower bone mass.
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PMID:Correlation of interleukin-6 serum levels with bone density in postmenopausal women. 909 98

Intracellular calcium is an important mediator of the cellular response in endotoxemia and shock. Here we investigated the effects of verapamil and diltiazem, two calcium entry blockers, on endotoxin (bacterial lipopolysaccharide, LPS)-induced production of pro- and anti-inflammatory cytokines and of nitric oxide in mice. LPS-induced interleukin-10 plasma levels were significantly enhanced, and circulating tumor necrosis factor-alpha concentrations were significantly suppressed in animals pretreated intraperitoneally with verapamil (10 mg/kg) or diltiazem (20 mg/kg). However, LPS-induced interleukin-6 levels were unaffected by the calcium antagonists. Similarly, LPS-induced production of nitrite/nitrate (breakdown products of nitric oxide) was not affected by verapamil and diltiazem. We conclude that calcium entry blockers; selectively modulate the production of some pro- and anti-inflammatory mediators in endotoxemia. These effects may contribute to the cytoprotective and anti-inflammatory effects of calcium entry blockers in shock and trauma.
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PMID:Calcium entry blockers increase interleukin-10 production in endotoxemia. 911 Apr 19

Our previous studies demonstrated that both in vivo and in vitro 3,4-dichloro-propionanilide (propanil) exposure inhibited interleukin-6 (IL-6) and tumor necrosis factor (TNF) production by adherent thioglycollate-elicited peritoneal cells (macrophages) after lipopolysaccharide (LPS) stimulation. In this study, we report that IL-6 and TNF-alpha message is reduced by propanil in a concentration-dependent pattern, yet the stability of cytokine mRNA is not affected. In addition, exposure of macrophages to propanil after a relatively short period of LPS stimulation significantly reduced the production of IL-6 and TNF. Determination of the intracellular Ca2+ levels demonstrates that LPS-induced Ca2+ release is abrogated in propanil-treated macrophages. However, the binding of LPS to macrophages is not affected. Measurement of inositol 1,4,5-triphosphate (IP3) demonstrates that propanil significantly increases the level and the duration of IP3 in macrophages. These results suggest that the inhibitory effect of propanil on macrophage cytokine production is associated with the early stages of LPS-mediated signal transduction in macrophages.
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PMID:Inhibitory effect of 3,4-dichloro-propionaniline on cytokine production by macrophages is associated with LPS-mediated signal transduction. 920 Dec 66

We previously reported that thrombin stimulates Ca2+ influx and activates phosphatidylcholine-hydrolyzing phospholipase D in osteoblast-like MC3T3-E1 cells. In this study, we investigated the effect of thrombin on interleukin-6 (IL-6) synthesis in these cells. Thrombin stimulated IL-6 synthesis dose-dependently in the range between 0.01 and 1 U/ml. The depletion of extracellular Ca2+ by EGTA suppressed the thrombin-induced IL-6 synthesis. TMB-8, an inhibitor of intracellular Ca2+ mobilization, also inhibited the IL-6 synthesis by thrombin. Propranolol, a phosphatidic acid phosphohydrolase inhibitor, enhanced the IL-6 synthesis by thrombin. Calphostin C, a highly potent and specific inhibitor for protein kinase C, significantly amplified the IL-6 synthesis by thrombin. The thrombin-induced IL-6 synthesis was enhanced in PKC down-regulated MC3T3-E1 cells. These results strongly suggest that thrombin stimulates IL-6 synthesis, which depends on intracellular Ca2+ mobilization mainly from extracellular space in osteoblasts, and that the IL-6 synthesis by thrombin is regulated due to thrombin-activated protein kinase C through phosphatidylcholine-hydrolyzing phospholipase D.
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PMID:Thrombin regulates interleukin-6 synthesis through phosphatidylcholine hydrolysis by phospholipase D in osteoblasts. 928 6

A new xenograft model of multiple myeloma (MM), where growth is strongly regulated by interleukin-6 (IL-6), was established in severe combined immunodeficiency (SCID) mice. In this model, endogenous IL-6 from SCID mice was ineffective at eliciting growth of the established human MM cell line KPMM2; these cells achieved autonomous growth through their autocrine secretion of IL-6. The etiopathology in this disease model is consistent with that of human MM. When greater than 3 x 10(6) KPMM2 cells were injected intravenously (IV), tumors developed in all mice and were predominantly localized in their bone marrow. Tumors were also apparent in the lymph nodes, but absent from other organs. Immunostaining of cell surface antigen (CD38) showed that more than 40% of bone marrow cells in femur were of myeloma origin in the advanced stage of tumor progression (day 37). Histologic analysis of these mice show that bone marrow was largely occupied by plasmablastic cells and bones had developed osteolytic lesions at multiple sites. Concurrently, there was a decrease in bone density throughout the body and a significant increase in ionized plasma calcium. M-protein was detected in the serum within 10 days after transplantation, which correlated with the tumor progression. Between 30 and 40 days after the transplantation, mice presented with a rapid and severe loss of body weight, hind leg paralysis, and fatigue. Subsequently, the mice died within a week. A single IV injection of 0.2 mg humanized anti-IL-6 receptor antibody (hPM1) into mice on the day after tumor transplantation substantially suppressed the elevation of serum M-protein and development of the tumor-associated abnormalities and significantly increased in the life span of tumor-bearing mice. Our data show the usefulness of this model to analyze the pathologic role of IL-6 in MM and the efficacy of targeting the IL-6 receptor in IL-6-dependent KPMM2 cells.
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PMID:New xenograft model of multiple myeloma and efficacy of a humanized antibody against human interleukin-6 receptor. 931 Apr 95

Parathyroid hormone (PTH) functions in part by regulating osteoblast cytokine expression. We recently demonstrated that PTH induced a rapid and transient increase in interleukin-6 (IL-6) mRNA expression in rat bones in vivo. To determine the molecular basis of this effect, we analyzed the human IL-6 promoter fused (-1,179 to +9) with the chloramphenicol acetyltransferase (CAT) reporter gene in stable transfections into human osteoblast-like osteosarcoma SaOS-2 cells. We compared the effects of PTH on IL-6 expression with adenylate cyclase activator forskolin, PKC activator phorbol 12-myristate 13-acetate (PMA), calcium ionophore A23187, interleukin-1 alpha (IL-1 alpha), prostaglandin E-2 (PGE-2), RS-66271 (a parathyroid hormone-related peptide analog), and platelet-derived growth factor-BB (PDGF-BB). Analyses of cell clones showed that IL-6 promoter expression was extremely low in the unstimulated state. Exposure to PTH (0.001-100 nM) for 12 h stimulated CAT expression in a dose-dependent manner (200-500% of control). Treatment with IL-1 alpha was more potent than PTH in inducing transcription of the IL-6 promoter (900-1,000%). Activation of the cAMP-PKA pathway by treatment with forskolin induced a comparable level of induction with PTH. Together, the effects of PTH and forskolin were additive. RS-66271, previously shown to have PTH-like effects, induced a comparable level of IL-6 promoter expression. When examined together, PTH+RS-66271 effects were comparable to PTH effects alone. Exposure to PGE-2, PMA, PDGF-BB, or A23187 for 12 h did not significantly alter IL-6 promoter expression. These results demonstrate PTH, forskolin, the PTHrP analog RS-66271, and IL-1 alpha stimulate IL-6 expression by stimulating gene transcription. The response to forskolin suggests that the messenger system mediated by PKA is sufficient to induce IL-6 expression.
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PMID:Parathyroid hormone (1-34)-mediated interleukin-6 induction. 932 32


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