Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The signal transduction events that follow the binding of lipopolysaccharide (LPS) to the macrophage cell surface are not well defined. In the current studies LPS was found to induce alterations in phosphorylation of monocyte proteins on tyrosine. Herbimycin A and genistein, inhibitors of tyrosine kinases, markedly attenuated LPS-induced tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) protein and mRNA production. Reciprocally, the tyrosine phosphatase inhibitor sodium orthovanadate enhanced LPS-induced production of TNF-alpha. LPS induced a concentration-dependent increase in tyrosine phosphorylation of several proteins, which paralleled and preceded the onset of LPS-induced TNF-alpha production. LPS stimulation had different but reproducible effects on three members of the src family of tyrosine kinases. Both Hck and Lyn kinase activity increased before the onset of TNF-alpha production, consistent with their participation in the observed LPS-induced tyrosine phosphoprotein accumulation. In contrast, Yes kinase activity was not affected. These observations were made at concentrations of LPS that required serum rich in LPS-binding protein and the monocyte surface antigen CD14 for TNF-alpha production. These data indicate that tyrosine kinases and phosphatases are involved in the signal transduction cascade by which LPS induces production of TNF-alpha and IL-6 by human monocytes, and suggest that Lyn and Hck are candidate participants in this process.
 ...
PMID:Lipopolysaccharide-induced cytokine production in human monocytes: role of tyrosine phosphorylation in transmembrane signal transduction. 751 9

Lipopolysaccharide (LPS), a major component of gram-negative cell walls, is a potent immunostimulator. Treatment of monocytes/macrophages in vitro with LPS induces the secretion of cytokines such as tumor necrosis factor-alpha and interleukin-1 alpha, -1 beta, and -6. LPS is thought to require LPS-binding protein or CD14 to act at low concentrations (< 100 ng LPS/ml). In the present study, rat ovarian thecal-interstitial cells (TIC) were cultured in a serum-free culture system (in the absence of LPS-binding protein or soluble CD14) and challenged with LPS. Treatment with LPS led to a dose-dependent (1-100 ng LPS/ml) decrease in LH-stimulated progesterone and androstenedione secretion. LPS had no effect on radiolabeled hCG binding to TIC homogenates or cAMP accumulation in culture medium. LPS treatment was associated with an increase in interleukin-6 bioactivity in the medium of thecal-interstitial cell cultures; however, tumor necrosis factor-alpha bioactivity was undetectable. Herbimycin A, an src tyrosine kinase inhibitor, blocked the actions of LPS and was associated with an increase in cAMP accumulation in TIC culture medium. The results suggest that LPS can act directly on ovarian thecal-interstitial cells and that this can occur in a LPS-binding protein/CD14-independent manner. The actions of LPS appear to be specific and require a nonreceptor tyrosine kinase.
 ...
PMID:Lipopolysaccharide inhibits rat ovarian thecal-interstitial cell steroid secretion in vitro. 758 4

We have investigated the roles of tyrosine kinase and protein kinase C activity in interleukin-1 beta-induced interleukin-6 production, using the U373 human astrocytoma cell line as a model system for astrocytes. Compounds known to inhibit tyrosine kinases were tested for effects on interleukin-6 production in U373 cells stimulated with interleukin-1 beta. Complete to nearly complete inhibition of interleukin-1 beta-induced interleukin-6 production was observed with the flavonoids genistein and quercetin, the bisindole alkaloids staurosporine and K-252a, or the tyrphostin AG879. Herbimycin A was a potent inhibitor but did not induce complete inhibition at saturating dose. Calphostin C, an inhibitor of protein kinase C, also completely inhibited interleukin-6 production. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate induced interleukin-6 production, and treatment with a combination of this phorbol ester and interleukin-1 produced synergistic stimulation. Prolonged exposure to phorbol ester eliminated subsequent stimulation by phorbol ester but only partially decreased interleukin-1-induced interleukin-6 and had no effect on the activities of selected inhibitors including calphostin C. We conclude that tyrosine kinase activity is essential for interleukin-1-induced interleukin-6 production in U373 astrocytoma cells and that activity of a phorbol ester-insensitive, atypical protein kinase C isozyme may also be involved.
 ...
PMID:Tyrosine kinase activity is essential for interleukin-1 beta--stimulated production of interleukin-6 in U373 human astrocytoma cells. 759 43

Interleukin-6 plays a key role in mediating acute-phase protein synthesis in hepatocytes. However, the mechanism of how interleukin-6 regulates aldolase B and albumin syntheses in hepatocytes is not completely understood. In this study, using primary cultured rat hepatocytes, we have shown that interleukin-6 down-regulates expressions of the aldolase B and albumin genes in a dose- and time-dependent manner. We examined whether the decrease in aldolase B and albumin mRNA expressions by interleukin-6 reflected transcriptional down-regulation or stability of the mRNA. Actinomycin D and cycloheximide did not affect the interleukin-6-mediated decrease in the expressions of both genes. These results suggest that the decreased expressions of both genes induced by interleukin-6 is controlled at the transcriptional level, and that it is due neither to increased degradation of mRNA nor to synthesis of new proteins. Protein kinases play a fundamental role in the intracellular signal transduction. To examine the interleukin-6 signal pathway(s) leading to the decrease of aldolase B and albumin mRNA expressions, we tested various kinds of protein kinase inhibitors in this system. Herbimycin A, an inhibitor of tyrosine kinase(s), prevented the decrease in the expression of aldolase B and albumin mRNAs by interleukin-6. H-7, an inhibitor of protein kinase C, prevented the decrease in the expression of albumin mRNA by interleukin-6, but did not induce recovery of that of aldolase B mRNA. These results suggest that a tyrosine kinase(s) or a herbimycin A-sensitive kinase(s) constitutes a common pathway for interleukin-6-mediated reduction of aldolase B and albumin mRNA expressions and that distinct pathways exist for the modes of expression of the two mRNAs.
 ...
PMID:Interleukin-6 down-regulates expressions of the aldolase B and albumin genes through a pathway involving the activation of tyrosine kinase. 762 25

Interleukin-6 (IL-6) is a multifunctional cytokine that is produced not only by a variety of normal cells but also by cancer cells. IL-6 produced by cancer cells stimulates the proliferation of these cancer cells in an autocrine/ paracrine manner and causes paraneoplastic syndromes including hypercalcemia, cachexia, and leukocytosis. We have reported previously that a human oral squamous cancer associated with hypercalcemia produces large amounts of IL-6, that animals bearing this cancer exhibit elevated levels of plasma IL-6, and that neutralizing antibodies to human IL-6 reverse hypercalcemia in tumor-bearing animals, indicating an important role of IL-6 in the hypercalcemia in this model. Because these cancer cells overexpress epidermal growth factor receptors (EGFR) with intrinsic tyrosine kinase (TK) activity similar to many other squamous cancers, we examined the effects of herbimycin A, a tyrosine kinase inhibitor, on IL-6 production and hypercalcemia in animals bearing this cancer to develop a new approach to treat the hypercalcemia associated with malignancy. Intraperitoneal administration (once a day for 2 days) of herbimycin A to cancer-bearing hypercalcemic mice reduced the plasma levels of human IL-6 and impaired the hypercalcemia. During 2-day treatment with herbimycin A, no changes were observed in tumor size. Of interest, plasma levels of mouse, but not human, soluble IL-6 receptors were also elevated. However, herbimycin A showed no effects on plasma levels of mouse soluble IL-6 receptors. Herbimycin A suppressed the tyrosine autophosphorylation of EGFR and IL-6 mRNA expression and production, all of which were stimulated by EGF. The data raise the possibility that TK inhibitors may be potential mechanism-based therapeutic agents for the treatment of hypercalcemia associated with squamous cancers which overexpress EGFR.
 ...
PMID:Herbimycin A, a tyrosine kinase inhibitor, impairs hypercalcemia associated with a human squamous cancer producing interleukin-6 in nude mice. 879 10

Cyclooxygenase-2 (COX-2) and tyrosine kinase, which are involved in the biosynthesis of prostaglandin E(2) (PGE(2)) in mouse calvarial osteoblasts, are stimulated by cytokine interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and/or interleukin-6 (IL-6). IL-1beta and IL-6 and, to a lesser extent, TNF-alpha, enhances COX-2 mRNA levels in calvarial osteoblasts. Simultaneous treatment with IL-6 and IL-1beta and TNF-alpha resulted in enhanced COX-2 mRNA levels accompanied by the cooperative stimulation of PGE(2) biosynthesis compared to cells treated with IL-1beta or TNF-alpha or IL-6 alone. In contrast, the presence of TGF-beta reduced COX-2 mRNA level, PGE(2) biosynthesis and bone resorption induced by IL-1beta, TNF-alpha, IL-6 or a combination thereof. However, neither IL-1beta, TNF-alpha, IL-6 nor a combination of IL-1beta, TNF-alpha, IL-6 enhanced COX-1 mRNA levels in calvarial osteoblasts. A novel Src tyrosine kinase inhibitor, Herbimycin A (HERB), reduced COX-2 mRNA levels as well as PGE(2) production induced by IL-1beta, TNF-alpha and IL-6 or a combination of IL-1beta, TNF-alpha, IL-6, whereas COX-1 mRNA levels remained unaffected. Finally, HERB was found to inhibit in vitro bone resorption. These results indicate that the cooperative effects of IL-beta, TNF-alpha, IL-6 on PGE(2) production are due to the enhanced expression of the COX-2 gene and that tyrosine kinase(s) are involved in COX-2 signal transduction in mouse calvarial osteoblasts. Thus, the Src family of kinase inhibitors may be useful in treating diseases associated with elevated bone loss.
 ...
PMID:Effects of TGF-beta, TNF-alpha, IL-beta and IL-6 alone or in combination, and tyrosine kinase inhibitor on cyclooxygenase expression, prostaglandin E2 production and bone resorption in mouse calvarial bone cells. 1531 72