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)

Auranofin (AF) is a sulphur-containing gold compound. Because of its anti-inflammatory and immunosuppressive activities, AF has been widely used for the therapeutic treatment of rheumatoid arthritis. However, little is known about its mechanism of action. To elucidate the molecular mechanism underlying the anti-inflammatory effect of AF, we studied the effects of AF on cellular responses to interleukin-6 (IL-6). In HepG2 human hepatoma cells, AF markedly inhibited IL-6-induced phosphorylation of janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3) and STAT3 translocation into the nucleus. Consistent with this, AF diminished IL-6-induced production of the acute-phase proteins, haptoglobin, fibrinogen, C3 complement and alpha(1)-acid glycoprotein, and gene expression of vascular endothelial growth factor, all of whose transcriptional activities are regulated by STAT3. The inhibitory activity of AF on STAT3 phosphorylation was also demonstrated in primary cells, i.e. fibroblast-like synoviocytes from rheumatoid arthritis patients, human umbilical vein endothelial cells and rat astrocytes. Auranofin-mediated inhibition of STAT3 phosphorylation was recovered by pretreatment with antioxidants containing thiol groups. These findings suggest that the anti-inflammatory action of AF is associated with a blockade of JAK1/STAT3 signalling. Thiol-group-reactive proteins may be involved in AF-induced suppression of JAK1/STAT3 phosphorylation.
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PMID:Auranofin blocks interleukin-6 signalling by inhibiting phosphorylation of JAK1 and STAT3. 1764 97

The hepatoprotective effect of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) has been well documented. However, reports on the role of IL-6/STAT3 in liver regeneration are conflicting probably due to the fact that the model of Stat3 knockout mice were complicated with obesity and fatty liver, which may cause some secondary effects on liver regeneration. To study the direct role of STAT3 and to circumvent the problems of obesity and fatty liver in liver regeneration, we generated conditional STAT3 knockout in the liver (L-Stat3(-/-)) using a transthyretin-driven Cre-lox method. The L-Stat3(-/-) mice were born with the expected Mendelian frequency and showed no obesity or other obvious phenotype. After partial hepatectomy, mortality in the L-Stat3(-/-) mice was significantly higher than the littermate Stat3(f/+) controls in the early time points (<24 h). Hepatocyte DNA synthesis in the survived L-Stat3(-/-) mice slightly decreased as compared with Stat3(f/+) mice at 40 h after partial hepatectomy, whereas similar hepatocyte DNA synthesis was found at other time points and liver mass could be completely recovered in the L-Stat3(-/-) mice. In another model of liver regeneration induced by subcutaneous injection of carbon tetrachloride (CCl(4)), hepatocyte DNA synthesis in the CCl(4)-treated L-Stat3(-/-) mice also decreased as compared with Stat3(f/+) mice at 40 h after injection but not at other time points. In addition, infiltration of neutrophils and monocyte increased in the liver of CCl(4)-treated L-Stat3(-/-) mice compared to wild-type mice. In conclusion, STAT3 is required for survival in the acute stage after 70% hepatectomy and plays a role in inflammatory reaction after hepatocyte necrosis. However, the hepatocytic STAT3 may have limited role in liver mass recovery although DNA synthesis may be impaired.
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PMID:Role of STAT3 in liver regeneration: survival, DNA synthesis, inflammatory reaction and liver mass recovery. 1766 Aug 47

Heme oxygenase-1 may exert cytoprotective effects. In this study we examined the sensitivity of heme oxygenase-1 knockout (HO-1(-/-)) mice to renal ischemia by assessing glomerular filtration rate (GFR) and cytokine expression in the kidney, and inflammatory responses in the systemic circulation and in vital extrarenal organs. Four hours after renal ischemia, the GFR of HO-1(-/-) mice was much lower than that of wild-type mice in the absence of changes in renal blood flow or cardiac output. Eight hours after renal ischemia, there was a marked induction of interleukin-6 (IL-6) mRNA and its downstream signaling effector, phosphorylated signal transducer and activator of transcription 3 (pSTAT3), in the kidney, lung, and heart in HO-1(-/-) mice. Systemic levels of IL-6 were markedly and uniquely increased in HO-1(-/-) mice after ischemia as compared to wild-type mice. The administration of an antibody to IL-6 protected against the renal dysfunction and mortality observed in HO-1(-/-) mice following ischemia. We suggest that the exaggerated production of IL-6, occurring regionally and systemically following localized renal ischemia, in an HO-1-deficient state may underlie the heightened sensitivity observed in this setting.
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PMID:Deficiency of heme oxygenase-1 impairs renal hemodynamics and exaggerates systemic inflammatory responses to renal ischemia. 1772 6

T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor gamma (ROR gamma) was shown to regulate Th17 differentiation; ROR gamma deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, ROR alpha, induced by transforming growth factor-beta and interleukin-6 (IL-6), which is dependent on signal transducer and activator of transcription 3. Overexpression of ROR alpha promoted Th17 differentiation, possibly through the conserved noncoding sequence 2 in Il17-Il17f locus. ROR alpha deficiency resulted in reduced IL-17 expression in vitro and in vivo. Furthermore, ROR alpha and ROR gamma coexpression synergistically led to greater Th17 differentiation. Double deficiencies in ROR alpha and ROR gamma globally impaired Th17 generation and completely protected mice against experimental autoimmune encephalomyelitis. Therefore, Th17 differentiation is directed by two lineage-specific nuclear receptors, ROR alpha and ROR gamma.
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PMID:T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. 1819 10

The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) oncoprotein has been shown to mediate activation of the signal transducer and activator of transcription 3 (STAT3). In the present study, we delineated the mechanism by which LMP1 stimulates STAT3 in a human nasopharyngeal carcinoma (NPC) cell line. LMP1 stimulated STAT3 Tyr 705-dependent nuclear accumulation, as well as the phosphorylation of STAT3 at both Tyr 705 and Ser 727. Treatment of cells with interleukin-6 neutralizing antibody inhibited the phosphorylation of STAT3 Tyr 705 and Ser 727. The differential phosphorylation of STAT3 was found to be a result of activation of Janus kinase 3 (JAK3) and extracellular signal-regulated kinase (ERK). The biological significance of JAK3-mediated activation of STAT3 Tyr 705 phosphorylation was further assessed by treating the cells with an inhibitor (WHI-P131) of JAK3. Inhibition of ERK activity by an inhibitor (PD98059) of MAPK/extracellular signal-regulated kinase kinase (MEK1) decreased the LMP1-induced activation of STAT3 Ser 727. Furthermore, immunohistochemical analysis showed an increased nuclear STAT3 Tyr 705 staining in LMP1-positive cells and STAT3 Tyr 705 phosphorylation related to NPC stages III and IV. Demonstration of the involvement of different kinases in LMP1-induced STAT3 activation supports the involvement of the JAK/STAT and mitogen-activated protein kinase (MAPK)/ERK signaling pathways in the regulation of STAT3 activation by LMP1.
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PMID:Phosphorylation and nuclear translocation of STAT3 regulated by the Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma. 1820 81

How diverse stimuli control hemopoietic lineage development is unknown. An early event during induction of macrophage differentiation in the myeloblastic leukemia M1 cell line by different stimuli, such as leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), is expression of the colony-stimulating factor-1 receptor (CSF-1R). We report that expression of active CSF-1R in M1 cells accelerated their subsequent terminal differentiation into macrophages in response to LIF and IL-6 when compared with cells lacking the CSF-1R or expressing the receptor with compromised kinase activity; however, there was no requirement for signaling through the CSF-1R, for example, via endogenous CSF-1, during the actual LIF-induced and IL-6-induced differentiation stage. Differences were noted in the signaling pathways downstream of the LIF receptor depending on the presence of the CSF-1R. Both LIF and IL-6 gave an additive response with CSF-1, consistent with LIF and IL-6 acting via a different signaling pathway (signal transducer and activator of transcription 3 dependent) than CSF-1 (extracellular signal-regulated kinase dependent). Based at least on this cell model, we propose that terminal macrophage differentiation involves a critical priming or deterministic phase in which signaling by the CSF-1R prepares a precursor population for subsequent rapid terminal macrophage differentiation by diverse stimuli. We also propose that expression and activation of the CSF-1R explain much prior literature on macrophage lineage commitment in M1 leukemic cells and may be important in controlling the progression of certain myeloid leukemias.
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PMID:The critical role of the colony-stimulating factor-1 receptor in the differentiation of myeloblastic leukemia cells. 1833 52

Macrophage-activating lipopeptide-2 (MALP-2) has been identified as the pathogen-associated molecular pattern of Mycoplasma fermentans, which causes stimulation of the innate immune system through the activation of the heterodimeric Toll-like receptors (TLRs) 2 and 6. Based on the reported protective effects of MALP-2 on healing of skin wounds, the central goal of this study was to evaluate the capacity of MALP-2 to induce a localized inflammatory response in an established model of a subcutaneous air pouch. Injections of MALP-2 into the pouch caused fever and some components of sickness behavior in rats. At the subcutaneous site of localized inflammation, a massive formation of tumor necrosis factor-alpha (TNF), interleukin-6 (IL-6), and prostaglandin E2 (PGE2) could be demonstrated in response to injections of MALP-2. Moderate amounts of IL-6 and PGE2 seemed to enter the systemic circulation of MALP-2-treated rats. The IL-6, which appeared in the blood after injection of MALP-2 into the air pouch was sufficient to cause a direct activation of brain cells in areas which lack a complete blood-brain barrier, namely in the sensory circumventricular organs (sCVOs), the organum vasculosum laminae terminalis (OVLT), the subfornical organ (SFO), and the area postrema (AP). The stimulation of cells at these brain sites was revealed by demonstration of a nuclear translocation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Corresponding to the circulating levels of IL-6, the nuclear STAT3 activation of cells within the sCVOs was much less pronounced after local subcutaneous when compared to systemic treatment with MALP-2. In conclusion, cells within the subcutaneous compartment are activated by the TLR2/6 agonist MALP-2. Fever and sickness behavior induced by injection of MALP-2 into subcutaneous tissue may, in part, be mediated by a spillover of IL-6 from the subcutaneous site of inflammation into the blood to cause activation of brain sites which are implicated in the manifestation of these illness responses.
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PMID:Macrophage-activating lipopeptide-2 (MALP-2) induces a localized inflammatory response in rats resulting in activation of brain sites implicated in fever. 1835 87

Granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) play key roles in regulating emergency granulopoiesis and inflammation, and are both negatively regulated by the inducible intracellular protein suppressor of cytokine signaling-3 (Socs3). Mice with Socs3 deleted specifically in hematopoietic cells succumb to severe neutrophil and macrophage-driven inflammation by 1 year of age, and responses to G-CSF are grossly exacerbated. In order to determine which elements of cellular responses to cytokines require Socs3, we have examined the differentiative and proliferative capacity of hematopoietic progenitor cells stimulated by G-CSF and IL-6. The differentiation of Socs3-deficient progenitor cells is skewed toward macrophage production in response to G-CSF or IL-6, whereas wild-type progenitor cells produce mainly neutrophils. The proliferative capacity of Socs3-deficient progenitor cells is greatly enhanced in response to G-CSF at all concentrations, but only at low concentrations for IL-6. Strikingly, synergistic responses to costimulation with stem cell factor and IL-6 (but not G-CSF) are lost at higher concentrations in Socs3-deficient progenitor cells. Cytokine-induced expression of transcriptional regulators including cebpb, Ets2, Bcl3, c-Myc, Jun, and Fosl2 are differentially regulated in Socs3-deficient cells. The tight regulation by Socs3 of signal transducer and activator of transcription 3 phosphorylation and gene transcription after cytokine receptor ligation significantly influences the fate of myeloid progenitor cells.
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PMID:Socs3 maintains the specificity of biological responses to cytokine signals during granulocyte and macrophage differentiation. 1840 Mar 61

The C-28 methyl ester of the oleane triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) induces apoptosis of human cancer cells by disrupting redox balance and is in clinical trials. CDDO-Me contains alpha,beta-unsaturated carbonyl groups that form reversible adducts with thiol nucleophiles. The present studies show that CDDO-Me blocks interleukin-6 (IL-6)-induced and constitutive activation of the Janus-activated kinase 1 (JAK1) in cells. In support of a direct mechanism, CDDO-Me forms adducts with JAK1 at Cys(1077) in the kinase domain and inhibits JAK1 activity. In concert with these results, CDDO-Me blocked IL-6-induced and constitutive activation of signal transducer and activator of transcription 3 (STAT3). Moreover, we show that CDDO-Me (a) binds directly to STAT3 by a mechanism dependent on the alkylation of Cys(259) and (b) inhibits the formation of STAT3 dimers. These findings indicate that CDDO-Me inhibits activation of the JAK1-->STAT3 pathway by forming adducts with both JAK1 and STAT3.
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PMID:Triterpenoid CDDO-methyl ester inhibits the Janus-activated kinase-1 (JAK1)-->signal transducer and activator of transcription-3 (STAT3) pathway by direct inhibition of JAK1 and STAT3. 1841 61

Hyper-IgE syndrome (HIES) is a complex primary immunodeficiency characterized by high serum IgE, chronic eczematoid dermatitis, and recurrent extracellular bacterial infections. Two types of HIES have been reported: type 1 and type 2. Type 1 HIES displays abnormalities in multiple systems, including the skeletal, dental, and immune systems, whereas type 2 shows abnormalities confined to the immune system. We recently identified hypomorphic mutations in the signal transducer and activator of transcription 3 (STAT3) gene in type 1 HIES and a null mutation in the tyrosine kinase 2 (Tyk2) gene, accompanied by susceptibility to intracellular bacteria in type 2 HIES. Analyses of cytokine responses in both types of HIES revealed that severe defects in the signal transduction for multiple cytokines, including interleukin-6 and interleukin-23, are leading to impaired T-helper type 17 function. These findings suggest that HIES is caused by the defects in multiple cytokine signals and that the susceptibility to various infections in HIES is associated with the T-helper type 17 defect.
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PMID:Genetic origins of hyper-IgE syndrome. 1868 2


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