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)

Internalization of pathogens by phagocytic cells triggers the innate immune response, which in turn regulates the acquired response. Phagocytes express a variety of receptors that are involved in recognition of pathogens, including (1) pattern recognition receptors (PRR), which recognize conserved motifs, (2) complement receptors (CR), which recognize complement-opsonized pathogens, and (3) Fc receptors (FcR), which recognize antibody-opsonized pathogens. Recognition of microbes is accompanied by the induction of multiple cell processes, including the production of proinflammatory and anti-inflammatory cytokines and chemokines. The objective of the present experiments was to use probes to known avian proinflammatory and anti-inflammatory cytokines and TaqMan technology to ascertain levels of cytokine gene expression in avian heterophils following receptor-mediated phagocytosis of either nonopsonized Salmonella enteritidis (SE), serum-opsonized SE, or IgG-opsonized SE. Expression of interleukin-6 (IL-6) and IL-8, considered in mammals as a proinflammatory chemokine, were upregulated following exposure to the nonopsonized or the opsonized SE. However, mRNA expression for IL-18 and interferon-gamma (IFN-gamma) was downregulated, and the expression of mRNA for the anti-inflammatory cytokine transforming growth factor-beta4 (TGF-beta 4) was upregulated. Interestingly, IL-1beta mRNA expression was significantly upregulated in heterophils that phagocytized either the nonopsonized SE via PRRs or IgG-opsonized SE via FcRs, whereas serum-opsonized SE phagocytized by CRs induced a downregulation of IL-1beta mRNA. These results suggest that signaling interactions initiated by receptor recognition of the microbe surface differentially regulate the induction of inflammatory cytokines in avian heterophils.
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PMID:Differential regulation of cytokine gene expression by avian heterophils during receptor-mediated phagocytosis of opsonized and nonopsonized Salmonella enteritidis. 1285 58

Interleukin-6 (IL-6) is a pro-inflammatory cytokine that plays an important role in the pathogenesis of inflammatory bowel disease. TGF-beta, a multifunctional cytokine, is a potent negative regulator of mucosal inflammation in the intestine. The aim of the present study is to determine possible cross-talk between IL-6 and TGF-beta signaling pathways. Model intestinal epithelial cell lines, Caco2-BBE were used. We show that TGF-beta receptor Type II is predominantly present in the basolateral membrane of intestinal epithelial cells. TGF-beta1 induces a time-dependent phosphorylation of Smad2 and co-immunoprecipitation of SMAD-2 with Smad-4 and its subsequently translocation to the nucleus. We show that pretreatment of cells with TGF-beta1 is associated with a down-regulation of IL-6 induced tyrosine phosphorylation of STAT1 and STAT3 and suppression of ICAM-1 expression. Furthermore, TGF-beta1 pretreatment resulted in a significant inhibition of IL-6 induced ICAM-1 promoter activity. TGF-beta mediated inhibition of IL-6 induced ICAM-1 expression was reversed by transfection with dominant negative Smad2 constructs. In conclusion, we show that: 1) TGF-beta receptor Type II is predominantly located on basolateral membrane and receptor stimulation activates Smad pathway; 2) TGF-beta1 down-regulates IL-6-induced tyrosine phoshorylation of STAT1 and STAT3 and ICAM-1 expression; and 3) Smad2 is required for the down-regulation of IL-6 signaling by TGF-beta. Collectively, our data demonstrate a cross-talk between TGF-beta and IL-6, and TGF-beta may play a role in the negative regulation of IL-6 signaling in intestinal epithelial cells.
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PMID:TGF-beta down-regulates IL-6 signaling in intestinal epithelial cells: critical role of SMAD-2. 1450 May 51

Excessive production of interleukin-6 (IL-6) and metalloproteinases (MMPs) have been implicated in the pathogenesis of rheumatoid arthritis. Lipoxin A4 (LXA4) and transforming growth factor beta 2 (TGF-beta 2), mediators with potential anti-inflammatory activities, were tested to determine how they affect IL-1 beta-dependent release of IL-6 and MMPs in human fibroblast like synoviocytes. The results showed dramatic differences between the mediators: TGF-beta 2 acted synergistically with IL-1 beta to stimulate IL-6 protein levels, whereas LXA4 inhibited IL-6 expression in dose- and time-dependent manner. Inhibition, by LXA4 was abrogated when cells were pre-incubated with antibody against the LXA4R whereas TGF-beta 2 by itself had no significant effect on IL-6 or MMP levels. LXA4, at nanomolar concentrations, altered the MMP-1 and MMP-3 expression levels of IL-1 beta and TGF-beta 2 stimulated fibroblast like synoviocytes at 5 days. Furthermore, IL-1 beta and TGF-beta 2 up-regulated LXA4R mRNA. These results demonstrate, for the first time, that LXA4Rs mediate the effects of LXA4 on inflammatory responses after combined stimulation of human fibroblast like synoviocytes with IL-1 beta and TGF-beta 2. These activities might constitute an important mechanism by which LXA4 regulates human synovial fibroblast activation.
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PMID:Lipoxin A4 counteracts synergistic activation of human fibroblast-like synoviocytes. 1500 Aug 62

We determined the association between clinical outcomes after heart transplantation and gene polymorphism in five cytokines (tumor necrosis factor-alpha, transforming growth factor (TGF)-beta, interleukin-10, interleukin-6, and interferon-gamma) reported to influence expression in vitro. Ninety-five patients were studied. Cytokine genotyping was performed by sequence specific priming polymerase chain reaction. Clinical outcomes studied in the first posttransplant year included: (1) documented viral, bacterial, or fungal infection; (2) cytomegalovirus infection; (3) acute cellular rejection (International Society for Heart and Lung Transplantation > or = grade IIIA); (4) time to first rejection episode; and (5) the development of allograft vasculopathy. Patients with the TGF-beta genotype 10 T/T 25 G/G or 10 T/C 25 G/G had a longer time to first rejection (median time to first rejection episode 321 days) than those with the TGF-beta genotype 10C/C 25 G/C or 10 C/C 25 C/C (median time to first rejection 88 days). There was a trend toward a higher frequency of the tumor necrosis factor-alpha genotype -308 G/A or A/A in patients without infection (19/59, 32%) as compared with patients with infection (5/31, 16%). In both cases, these differences failed to reach significance when adjusted for multiple comparisons. No other significant association was found with clinical outcomes and polymorphisms in the five cytokine genes studied in this population.
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PMID:The effect of recipient cytokine gene polymorphism on cardiac transplantation outcome. 1504 Nov 64

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.
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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

Chronic liver injury causes liver regeneration, resulting in fibrosis. The proinflammatory cytokine tumor necrosis factor (TNF) is involved in the pathogenesis of many acute and chronic liver diseases. TNF has pleiotropic functions, but its role in liver fibrosis has not been clarified. Chronic repeated injection of CCl4 induces liver fibrosis in mice. We examined whether signaling through TNF receptors was critical for this process, using mice lacking either TNF receptor (TNFR) type 1 or TNFR type 2 to define the pathophysiologic role of TNFR signals in liver fibrosis. Liver fibrosis caused by chronic CCl4 exposure was TNF-dependent; histological fibrosis was seen in wild-type (WT) and TNFR-2 knockout (KO) mice, but not in TNFR-1 KO mice. Furthermore, a marked reduction in procollagen and TGF-beta synthesis was observed in TNFR-1 KO mice, which also had little detectable NF-kappa B, STAT3, and AP1 binding, and reduced levels of liver interleukin-6 (IL-6) mRNA compared to WT and TNFR-2 KO mice. In conclusion, our results indicate the possibility that NF-kappa B, STAT3, and AP1 binding by signals transduced through TNFR-1 plays an important role in liver fibrosis formation.
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PMID:Lack of tumor necrosis factor receptor type 1 inhibits liver fibrosis induced by carbon tetrachloride in mice. 1576 Jun 80

Anti-bone resorption properties of the Korean herbal medicine, Yukmi-jihang-tang (YJ), which is comprised of seven herbs such as Rehmannia glutinosa Libosch, Dioscorea japonica THUNB, Cornus officinalis SIEB et. ZUCC, Smilax glabra ROXB, Paeonia suffruticosa ANDR, Alisma platago-aquatica var. orientale SAMUELS and Hominis placenta, were investigated. Cyclooxygenase-2 (COX-2) and tyrosine kinase involve on prostaglandin E2 (PGE2) production in mouse calvarial osteoblasts 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, enhanced COX-2 mRNA levels in calvarial osteoblasts. TGF-beta, YJ (100microg/ml) and their combinations of YJ+TGF-beta reduced the COX-2 mRNA level, PGE2 biosynthesis and bone resorption induced by IL-1beta, TNF-alpha, IL-6 or their combination. Finally, YJ inhibits in vitro and in vivo bone resorption by inhibition of phosphorylation of peptide substrates. The parathyroid hormone-induced bone resorption in mouse fetal long bone cultures was inhibited with an IC(50) of 16microg/ml. YJ dose-dependently reduced the hypercalcemia induced in mice by IL-1beta and partly prevented bone loss and microarchitectural changes in young ovariectomized rats, showing that the protective effect on bone was exerted via the inhibition of bone resorption. These results indicate that the synergy between IL-beta, TNF-alpha, IL-6 on PGE2 production is due to an enhanced gene expression of COX-2 and that tyrosine kinase(s) are involved in the signal transduction of COX-2 in mouse calvarial osteoblasts. Thus, YJ as a possible Src family kinase inhibitor may be useful for the treatment of diseases associated with elevated bone loss. This result also suggested that the YJ extracts is effective for bone resorptive action in bone cells.
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PMID:Herbal formulation, Yukmi-jihang-tang-Jahage, regulates bone resorption by inhibition of phosphorylation mediated by tyrosine kinase Src and cyclooxygenase expression. 1651 8

The aim of our study was to investigate the influence of angiotensin-converting enzyme (ACE) inhibition and angiotensin II receptor blockage on the renal function by light microscopic and immunohistochemical findings in a rat model of tacrolimus nephrotoxicity. Thirty-two male Wistar rats were divided into four groups of eight: G1 = control group; G2-G3, G4 = Tacrolimus (Tac) 1 mg/kg/d intraperitoneally (ip); G3 (Tac + Q) = ip Tac and peroral quinapril 10 mg/kg; and G4 (Tac + V) = Tac and valsartan 40 mg/d. Serum blood urea nitrogen (BUN), creatinine, and creatinine clearance were measured before and at the end of the study period. Renal tissues were assessed for light microscopic findings of tacrolimus toxicity. Transforming growth factor-beta, VEGF, PDGF, BMP-7, and interleukin-6 (IL-6) expression were semiquantitatively scored after immunohistochemical staining. At the end of the study period serum BUN and creatinine levels were increased in all groups, but creatinine clearance was not significantly changed between the groups. Afferent arteriolopathy was significantly less pronounced in G3 versus G2 and G4. Interstial fibrosis was significantly less pronounced in G3 and G4 versus G2. TGF-beta, PDGF, and IL-6 expression were significantly increased in G2, G3, and G4 compared to G1, and in G2 compared to G3 and G4. BMP-7 expression was significantly decreased in G2, G3, and G4 compared to G1, whereas the differences between G2, G3, and G4 failed to reach statistical significance. In conclusion, the results of our study suggested that renin angiotensin inhibition down-regulates fibrogenic cytokine expression in rats displaying tacrolimus nephrotoxicity.
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PMID:Inhibition of the renin angiotensin system decreases fibrogenic cytokine expression in tacrolimus nephrotoxicity in rats. 1654 54

Liver injury induces activation of hepatic stellate cells (HSCs) comprising expression of receptors, proliferation, and extracellular matrix synthesis triggered by a network of cytokines provided by damaged hepatocytes, activated Kupffer cells and HSCs. While 6 days after bile duct ligation in rats TGF-beta inhibited DNA synthesis in HSCs, it was enhanced after 14 days, indicating a switch from suppression to DNA synthesis stimulation during fibrogenesis. To delineate mechanisms modulating TGF-beta function, we analyzed crosstalk with signaling pathways initiated by cytokines in damaged liver. Lipopolysaccharide and tumor necrosis factor-alpha enhanced proliferation inhibition of TGF-beta, whereas interleukin-6, oncostatin M, interleukin-1alpha, and interleukin-1beta did not. Hepatocyte growth factor (HGF) counteracted TGF-beta dependent inhibition of DNA synthesis in quiescent HSCs. Since expression of c-met is induced during activation of HSCs and HGF is overrepresented in damaged liver, crosstalk of HGF and TGF-beta contributes to loss of TGF-beta dependent inhibition of DNA synthesis in HSCs.
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PMID:Loss of TGF-beta dependent growth control during HSC transdifferentiation. 1720 47

The aim of our study was to investigate the effects of subcutaneous desferrioxamine (DFX) and oral deferiprone (L1) therapy on bone metabolism markers in patients with thalassemia major. We studied 17 patients with thalassemia receiving long-term treatment with desferrioxamine, 20 patients receiving long-term treatment with deferiprone, and 15 healthy age-matched controls. The following investigations were performed: a) intact parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D] as endocrine parameters; b) alkaline phosphatase (ALP), bone alkaline phosphatase (BALP), osteocalcin (OC); c) bone resorption biochemical markers in serum and urine pyridinium crosslinks: hydroxylysyl-pyridinoline (HP) and lysyl-pyridinoline (LP); d) serum levels of cytokines and growth factors: transforming growth factor-beta1 (TGFbeta1), insulin-like growth factor-I (IGF-I), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-a (TNFalpha); e) serum levels of IGF binding protein-3 (IGFBP-3). No significant differences among all studied variables were found in patients with thalassemia treated with desferrioxamine or deferiprone. In contrast, significant differences were found between patients with thalassemia and the control group: intact PTH was significantly lower in patients with thalassemia than in the controls (p < 0.0005), and a significant increase in ALP and BALP (p < 0.0005), but not in OC, was found in the patient group. With regard to bone resorption and remodeling markers, the urinary excretion of pyridinium crosslinks was higher in patients with thalassemia for HP fraction (p < 0.0005) and LP fraction (p = 0.002), as well as TGFbeta (p = 0.001). In contrast, IGF-I and IGFBP-3 were reduced when compared with controls. In conclusion, the study of bone metabolism markers in adult patients with thalassemia reveals a complex behavior with an increase in bone resorption indexes. Bone formation did not appear to be impaired. In particular, TGFbeta1 was higher in patients with thalassemia receiving L1 treatment.
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PMID:Chelation therapy and bone metabolism markers in thalassemia major. 1722 62


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