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)

Our purpose was to determine if cytokines are produced systemically during acute pancreatitis. Proinflammatory cytokines are elevated during acute pancreatitis and have been implicated in the progression of pancreatitis-associated multiple organ dysfunction. Whether these mediators are produced within all tissues or very few specific organs is not known. Edematous pancreatitis was induced in adult male mice by IP injection of cerulein. Necrotizing pancreatitis was induced in young female mice by feeding a choline-deficient, ethionine supplemented diet. Animals were sacrificed as pancreatitis worsened, with multiple organs prepared for tissue mRNA and protein analysis by RT-PCR and immunoblotting. Pancreatitis severity was established by histologic grading and serum amylase and lipase. There was no cytokine mRNA or protein detectable prior to the induction of pancreatitis. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1 beta) mRNA and protein were detected within the pancreas early in the course of pancreatitis in both models, coinciding with the development of hyperamylasemia (both P < 0.001). Interleukin-6 was produced in the pancreas after pancreatitis was more fully developed (P < 0.001). IL-1 beta and TNF-alpha were subsequently produced in large amounts in lung, liver, and spleen but never within kidney, cardiac muscle, or skeletal muscle. A significant delay between pancreatic and distant organ cytokine production was always observed. It is concluded that proinflammatory cytokines are produced within the pancreas and within organs known to develop dysfunction during severe pancreatitis. Cytokine production is tissue specific, correlates with disease severity, and occurs within the pancreas first and subsequently within distant organs.
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PMID:Tissue-specific cytokine production during experimental acute pancreatitis. A probable mechanism for distant organ dysfunction. 928 48

Tumor necrosis factor (TNF) has a specific gene-inducing activity on many cell types and exerts a cytotoxic effect on a number of tumor cell lines. However, several tumor cell types are resistant to TNF-induced effects, and some of these produce TNF. We previously demonstrated that introduction of an exogenous TNF gene in the TNF-sensitive cell line L929sA induced autocrine TNF production and unresponsiveness to the cytotoxic activity of TNF. This resistance required biologically active TNF and was correlated with complete down-modulation of the TNF receptors on the cell surface. We have now characterized this process in more detail. The role of expression of the membrane-bound TNF proform and its subsequent proteolytic processing in the induction of TNF unresponsiveness was investigated. Exchange of the TNF presequence for the signal sequence of interleukin-6 resulted in production of secreted TNF, but not in induction of TNF resistance. On the other hand, expression of non-secretable, membrane-bound TNF generated complete TNF unresponsiveness. To explore whether the requirement for anchoring reflected a specific functional role of the TNF presequence, the latter was replaced by the membrane anchor of trimeric chicken hepatic lectin. Expression of this construct induced complete TNF unresponsiveness. Hence, the role of the TNF presequence in the induction of TNF unresponsiveness only involves its function as a membrane anchor, which permits oligomerization of the TNF molecule into a biologically active homotrimer.
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PMID:Induction of unresponsiveness to tumor necrosis factor (TNF) after autocrine TNF expression requires TNF membrane retention. 945 42

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine that elicits a large number of biological effects. However, the intracellular signaling mechanisms that are responsible for the TNF-alpha effects remain largely unknown. We have previously demonstrated that cultured mouse Sertoli cells, after TNF-alpha treatment, increase the surface expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and interleukin-6 (IL-6) production (Riccioli, A., Filippini, A., De Cesaris, P., Barbacci, E., Stefanini, M., Starace, G., and Ziparo, E. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 5808-5812). Here, we show that, in cultured Sertoli cells, TNF-alpha activates the mitogen-activated protein kinase pathway (p38, c-Jun N-terminal protein kinase/stress-activated protein kinase, and the p42/p44 mitogen-activated protein kinases) as revealed by an increased phosphorylation of p38, activating transcription factor-2, c-Jun, and Elk-1. Furthermore, our data indicate that the biological effects induced by TNF-alpha in Sertoli cells (enhancement of ICAM-1, VCAM-1, and IL-6 expression) depend on the activation of different signaling pathways. SB203580, a highly specific p38 inhibitor, does not affect ICAM-1 and VCAM-1 expression, but strongly inhibits IL-6 production. Moreover, interferon-gamma, which up-regulates adhesion molecule expression and reduces IL-6 production, does not induce phosphorylation of p38. Our data strongly support the hypothesis that, in response to TNF-alpha, activation of p38 leads to IL-6 production, whereas ICAM-1 and VCAM-1 expression could be induced by activation of the c-Jun N-terminal protein kinase/stress-activated protein kinase pathway.
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PMID:Tumor necrosis factor-alpha induces interleukin-6 production and integrin ligand expression by distinct transduction pathways. 951 59

The effect of pentoxifylline (PTX) was tested for its capacity to modulate cytokine responses during therapy of severe Plasmodium falciparum malaria in a placebo-controlled, randomized study in 45 adult patients in Bangkok, Thailand. The patients received standard antimalarial treatment with artesunate (120 mg intravenously given immediately, then 60 mg every 12 hr for a total dose of 600 mg). The patients received either low-dose PTX (20 mg/kg/day, n = 15), high-dose PTX (40 mg/kg/day, n = 15), or placebo (n = 15) as continuous infusion for the first three days of antimalarial treatment. Tumor necrosis factor (TNF) and interleukin-6 (IL-6) plasma levels were markedly elevated in all patients prior to treatment. After 6 hr of high-dose PTX treatment, TNF and IL-6 levels significantly decreased while an increase in TNF and IL-6 levels was seen after 6 hr of low-dose PTX or placebo treatment (P < 0.01). After 12 and 24 hr of high-dose PTX infusion, TNF-receptor plasma concentrations were lower than in low-dose PTX- or placebo-treated patients (P < 0.01), whereas no differences between the groups with regard to IL-6 receptor levels were observed. We conclude that 40 mg/kg/day of PTX reduces plasma levels of TNF, IL-6, and TNF-receptor in patients with severe malaria. Whether this reduction improves clinical outcome remains to be determined.
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PMID:Effect of pentoxifylline on cytokine patterns in the therapy of complicated Plasmodium falciparum malaria. 954 16

Tumor necrosis factor-alpha (TNF-alpha) plays a key role in inflammatory diseases such as rheumatoid arthritis and in postmenopausal osteoporosis. In various tissues, TNF-alpha action is mediated by a transcription factor, nuclear factor-kappa B (NF-kappaB). However, little is known about how TNF-alpha exerts its action in osteoblasts. We thus examined the effect of TNF-alpha on the activation of NF-kappaB in rat osteoblast-like osteosarcoma cells (ROS17/2.8). Electrophoretic mobility shift assay revealed that the activation of the p50-p65 heterodimer NF-kappaB was induced by TNF-alpha as early as 15 minutes followed by a persistent activation for 48 h. When the binding activity of NF-kappaB in cytosol was examined using detergents that dissociate NF-kappaB from an inhibitory protein IkappaB, it decreased during the initial 30 minutes and then increased to the unstimulated level. Northern blot analysis revealed a marked increase in the mRNA levels of p105, a precursor of p50, 6 h after TNF-alpha and a gradual increase in p65 mRNA levels during the initial 1 h. Significant increase in both mRNA levels continued until 24 h after TNF-alpha. These results suggest that the rapid activation of NF-kappaB by TNF-alpha is mainly due to the nuclear translocation of NF-kappaB pre-existing in cytosol, and that the subsequent increase in the expression of p50 and p65 may result in the persistent activation of NF-kappaB during TNF-alpha stimulation. TNF-alpha also increased the mRNA levels of interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1). An antioxidant, N-acetyl-L-cysteine, significantly attenuated the TNF-alpha-dependent increase in these mRNAs, and simultaneously reduced the activation of NF-kappaB by TNF-alpha, indicating that NF-kappaB mediates the TNF-alpha-dependent expression of IL-6 and ICAM-1 in ROS17/2.8 cells. These results suggest that the activation of NF-kappaB by TNF-alpha may play an important role in the production of cytokines and cell adhesion molecules from osteoblasts, leading to the promotion of bone resorption and inflammation.
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PMID:TNF-alpha increases expression of IL-6 and ICAM-1 genes through activation of NF-kappaB in osteoblast-like ROS17/2.8 cells. 971 98

Intravenous immunoglobulin (IVIg) is increasingly used in the treatment of autoimmune and inflammatory diseases, including vasculitides and Kawasaki disease. However, the outcome of IVIg interaction with endothelial cells of the vascular bed is not clear as yet. We have investigated the effect of IVIg on the in vitro activation of human endothelial cells, as assessed by cell proliferation and reverse transcription-polymerase chain reaction-detected expression of mRNA coding for adhesion molecules (intercellular adhesion molecule-1 and vascular cellular adhesion molecule-1), chemokines (monocyte chemoattractant protein-1, macrophage colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor), and proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6). IVIg inhibited proliferation of endothelial cells in a time-dependent manner. This effect was dependent on both Fc and F(ab')2 fragments of the immunoglobulin molecule and was fully reversible. Tumor necrosis factor-alpha and interleukin-1beta also inhibited thymidine incorporation, but to a lesser degree. IVIg had no effect on basal levels of mRNA coding for the adhesion molecules, chemokines, and proinflammatory cytokines. IVIg fully down-regulated the expression induced by tumor necrosis factor-alpha or interleukin-1beta of mRNA coding for these molecules. Thus, blockade of cellular proliferation and of cytokine-induced expression of adhesion molecules, chemokines, and cytokines may explain the therapeutic effect of IVIg in vascular and inflammatory disorders.
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PMID:Modulation of endothelial cell function by normal polyspecific human intravenous immunoglobulins: a possible mechanism of action in vascular diseases. 977 57

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine that orchestrates an array of local and systemic effects. For instance, acute exposure to a high dose of TNF-alpha results in septic shock and fever. We have used interleukin-1beta (IL-1beta)- and interleukin-6 (IL-6)-deficient mice, along with their wild-type equivalents, to define a role for TNF-alpha in fever. Briefly, the mice produced prostaglandin E2-dependent fevers in response to recombinant murine TNF-alpha (rmTNF-alpha). Furthermore, rmTNF-alpha (12 microgram/mouse ip) triggered a febrile response in IL-1beta-deficient mice as well as in their corresponding wild-type controls. In contrast, the IL-6-deficient mice were resistant to rmTNF-alpha (4.5 microgram/mouse ip), although their wild-type counterparts readily mounted a fever. In the IL-6-deficient mice, moreover, the febrile response to rmTNF-alpha could be restored by a central administration of rat recombinant IL-6 (500 ng/mouse icv). We thus conclude that TNF-alpha can trigger fever independent of IL-1beta but dependent on IL-6. We also suggest that central, rather than peripheral, IL-6 (plasma IL-6 was measured 2 h after pyrogenic challenge) is essential in TNF-alpha-induced fever.
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PMID:IL-6 is essential in TNF-alpha-induced fever. 984 93

To investigate the ability of recombinant human interleukin 10 (rhuIL-10) to suppress the release of inflammatory mediators from lipopolysaccharide (LPS)-stimulated equine macrophages, rhuIL-10 was added to equine peritoneal macrophage monolayers at concentrations of 0, 0.1, 1, 10, or 100 ng/ml. Thirty minutes later, LPS (E. coli O55:B5) was added at final concentrations of 0, 1, 10, 100 ng/ml. Macrophages were incubated for 16 h at 37 degrees C, then supernates were harvested and assayed for tumor necrosis factor (TNF) activity (L929 cytotoxicity), interleukin-6 (IL-6) activity (B9 proliferation), prostaglandin E2 concentration (ELISA), and nitric oxide (Griess reaction for nitrite). Preincubation of LPS-stimulated peritoneal macrophages with rhuIL-10 caused significant (P<0.05) reduction in secretion of TNF, IL-6, and PGE2, in a dose-dependent manner. Of the inflammatory mediators, TNF was most sensitive to the effects of rhuIL-10. At concentrations of rhuIL-10> or =1 ng/ml, TNF activity in the supernate was inhibited significantly at all concentrations of LPS. At one or more LPS concentrations, there was significant inhibition of each mediator in the presence of 1 ng rhuIL-10/ml and, at 100 ng/ml, rhuIL-10 significantly inhibited production of each mediator at all LPS concentrations tested. When data were expressed as a percentage of control values and pooled across all LPS concentrations, both PGE2 and TNF values were significantly reduced at rhuIL-10 concentrations of > or =1 ng/ml, whereas IL-6 was inhibited significantly at concentrations of > or =10 ng rhuIL-10/ml. Tumor necrosis factor production was more completely suppressed (7.8% of control) by the highest concentration of rhuIL-10(100 ng/ml) than was PGE2 (27.2%) or IL-6 (43.8%). Nitrite was not detected in any supernate from peritoneal macrophage monolayers.
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PMID:Human interleukin 10 suppresses production of inflammatory mediators by LPS-stimulated equine peritoneal macrophages. 984 16

Stress mediators play a major role in inducing the hypermetabolic stress state in the liver after major injuries. The majority of studies on the effect of mediators on hepatocytes have focused on single factor effects or on the effect of very complex additives (e. g., serum), and there are no reports which have rigorously identified specific interactions between stress mediators. We used a factorial design experimental approach to evaluate the effects of a four to five day exposure to hormone (glucagon, hydrocortisone, and epinephrine) and cytokine [tumor necrosis factor-alpha (TNF-alpha) interleukin-1beta (IL-1beta) and interleukin-6 (IL-6)] stress mediators on stable cultures of rat hepatocytes. Both individual-factor effects and two factor interactions on the metabolism of urea, glucose, lactate, ketone bodies, albumin, and fibrinogen were evaluated. The cultured hepatocyte model exhibited physiologic responses to the applied stress mediators. While hydrocortisone and epinephrine had no effect, glucagon induced an increase in glucose and urea synthesis. Interleukin-6 increased fibrinogen and decreased albumin production. Furthermore, IL-6 and glucagon caused an increase in the ketone-body ratio (KBR = [acetoacetate]/[beta-hydroxybutyrate]), which is in equilibrium with the intramitochondrial NAD+/NADH. Tumor necrosis factor-alpha and IL-1beta, on the other hand, decreased the KBR. An important two-factor interaction between IL-1beta and IL-6 was identified, namely that IL-1beta effectively negates the positive effect of IL-6 on the KBR when both are present. These results provide further understanding of the effect of stress mediators on hepatic function and metabolism. These effects may have important implications in the pathogenesis of progressive organ dysfunction which often follows prolonged inflammatory states triggered by major injuries.
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PMID:Metabolic effects of stress mediators on cultured hepatocytes. 1019 93

The monocyte/macrophage (Mphi is central in the regulation of the immune response in states of trauma and sepsis. Because monocyte subsets, characterized by expression of the Fc-receptor (FcR), were shown to play distinct immunologic roles in trauma, it was the objective of this study to assess insights into the functional role of FcR positive (FcR+) and negative (FcR-) subclasses in surgical sepsis. In a prospective study, peripheral blood Mphi from 20 septic patients and 10 healthy volunteers were evaluated on consecutive days after the onset of sepsis. FcR+/- subsets were separated by rosetting with antibody-coated human erythrocytes. Receptor expression and synthesis of proinflammatory cytokines were used to evaluate the functional role of these cells. We demonstrated a significant monocytosis (350%; p<.01) and suppression of human lymphocyte antigen (HLA-DR) expression (35%; p<.05). Synthesis of Interleukin-1beta (IL-1beta; e.g., Day 1: 230+/-30 pg/mL) and Interleukin-6 (IL-6; e.g., Day 1: 1920+/-350 U/mL) were significantly higher (p<.05) in FcR+ subsets than in controls (IL-1beta: 100+/-5 pg/mL; IL-6: 353+/-75 U/mL). Tumor necrosis factor-alpha (TNF-alpha) was elevated in FcR+ monocytes but did not reach a significant value. Interleukin-8 (IL-8) synthesis showed only on Day 1 and in controls significant differences in FcR+ and FcR- cells (Day1: FcR-: 19.6+/-4.1 nM; FcR+: 9+/-4.3 nM). Sepsis results in a significant shift toward FcR+ monocytes. This cell population is characterized by high proinflammatory cytokine synthesis. The extent of this shift seems to identify a group of high risk septic patients that might benefit from immunomodulatory therapy.
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PMID:Evaluation of Fc-receptor positive (FcR+) and negative (FcR-) monocyte subsets in sepsis. 1022 Feb 97


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