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)

Radix Linderae, the dry roots of Lindera aggregata (Sims) Kosterm (L. strychnifolia Vill), has been long-term used in traditional Chinese medicine for treating various diseases, and alkaloids are believed to be the main active components. Previously, we reported that the total alkaloids from Radix Linderae (TARL) could effectively alleviate inflammation and protect joints from destruction in mouse collagen-induced arthritis, an animal model of human rheumatoid arthritis (RA). To get insight into the underlying mechanisms of TARL, the present study was performed to investigate the effects of TARL on the activation of macrophages and resultant production of inflammatory mediators. In vitro, TARL concentration-dependently prevented the production of nitric oxide, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), as well as the expressions of iNOS, IL-1beta and TNF-alpha mRNA in RAW 264.7 cells stimulated by lipopolysaccharide (LPS). However, it showed little effect on the production of interleukin-6 (IL-6) and the expression of IL-6 mRNA. Signal transduction studies showed that TARL significantly down-regulated the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAP kinase rather than c-jun NH(2)-terminal kinase (JNK). Additionally, TARL prominently decreased LPS-induced activation of IKKalpha and phosphorylation of p65 on serine 276, but had little impact on the phosphorylation and degradation of IkappaBalpha. In summary, our results demonstrate that TARL exhibits inhibitory effects on the production of inflammatory mediators from macrophages via blocking NF-kappaB and MAPKs signaling pathways. The findings provide a plausible explanation for the therapeutic efficiency of TARL on the inflammation and joint destruction in RA.
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PMID:Total alkaloids from Radix Linderae prevent the production of inflammatory mediators in lipopolysaccharide-stimulated RAW 264.7 cells by suppressing NF-kappaB and MAPKs activation. 1924 28

Several sesquiterpene lactones that have been isolated from medicinal plants are known to have many pharmacological activities. In this study, we investigated the anti-inflammatory effects of zedoarondiol, a sesquiterpene lactone isolated from the rhizoma of Curcuma heyneana, in lipopolysaccharide (LPS)-stimulated macrophage cells. Zedoarondiol dose-dependently inhibited LPS-stimulated nitric oxide (NO), prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta) productions in RAW 264.7 macrophage and in mouse peritoneal macrophage cells. Consistent with these findings, in RAW 264.7 cells, zedoarondiol suppressed the LPS-stimulated protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and the mRNA expressions of iNOS, COX-2, TNF-alpha, IL-6, and IL-1beta in a concentration-dependent manner. Moreover, molecular data revealed that zedoarondiol inhibited LPS-stimulated DNA binding activity and the transcription activity of nuclear factor-kappa B (NF-kappaB), and this effect was accompanied by decreases in the degradation and phosphorylation of inhibitory kappaB (IkappaB)-alpha, and in the subsequent blocking of NF-kappaB translocations to the nucleus. Furthermore, zedoarondiol attenuated the phosphorylations of IkappaB kinase (IKK), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), and c-Jun N-terminal kinase (JNK) in LPS-stimulated RAW 264.7 cells. Taken together, the findings of the present study indicate that zedoarondiol inhibits iNOS, COX-2, and pro-inflammatory cytokine expressions by suppressing the phosphorylations of IKK and MAPKs, and by subsequently inactivating the NF-kappaB pathway. These relations reveal, in part, the mechanism underlying the anti-inflammatory properties of zedoarondiol.
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PMID:Zedoarondiol isolated from the rhizoma of Curcuma heyneana is involved in the inhibition of iNOS, COX-2 and pro-inflammatory cytokines via the downregulation of NF-kappaB pathway in LPS-stimulated murine macrophages. 1939 40

Thromboxane A(2) (TXA(2)), a potent inducer of platelet aggregation and smooth muscle contraction, exerts its action through TXA(2) receptor (TP). There are two alternative splicing variants of TP, TP alpha and TP beta. To clarify the signal transduction of TP pathway, we searched for putative TP binding proteins using a yeast two-hybrid system with the C-terminal region of TP alpha or TP beta as bait. We found KIAA1005 as a novel interacting protein of the TP alpha and TP beta C-terminal region (TP interacting protein, TPIP). KIAA1005/TPIP was co-immunoprecipitated with TP alpha or TP beta in HEK293 cells expressing myc-KIAA1005/TPIP and FLAG-TP isoforms. Expression analysis showed a ubiquitous expression pattern of KIAA1005/TPIP mRNA, including prominent expression in the thymus. Furthermore, TP-mediated phosphoinositide hydrolysis, phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and interleukin-6 production were reduced by the expression of KIAA1005/TPIP. The expression of KIAA1005/TPIP decreased cell-surface TP alpha and TP beta levels. Thus, we show for the first time that KIAA1005/TPIP is a novel TP interacting protein that regulates TP-mediated signal transduction negatively.
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PMID:Thromboxane A2-induced signal transduction is negatively regulated by KIAA1005 that directly interacts with thromboxane A2 receptor. 1946 61

It is well known that cancer cells secrete angiogenic factors to recruit and sustain tumor vascular networks. However, little is known about the effect of endothelial cell-secreted factors on the phenotype and behavior of tumor cells. The hypothesis underlying this study is that endothelial cells initiate signaling pathways that enhance tumor cell survival and migration. Here, we observed that soluble mediators from primary human dermal microvascular endothelial cells induce phosphorylation of signal transducer and activator of transcription 3 (STAT3), Akt, and extracellular signal-regulated kinase (ERK) in a panel of head and neck squamous cell carcinoma (HNSCC) cells (OSCC-3, UM-SCC-1, UM-SCC-17B, UM-SCC-74A). Gene expression analysis demonstrated that interleukin-6 (IL- 6), interleukin-8 (CXCL8), and epidermal growth factor (EGF) are upregulated in endothelial cells cocultured with HNSCC. Blockade of endothelial cell-derived IL-6, CXCL8, or EGF by gene silencing or neutralizing antibodies inhibited phosphorylation of STAT3, Akt, and ERK in tumor cells, respectively. Notably, activation of STAT3, Akt, and ERK by endothelial cells enhanced migration and inhibited anoikis of tumor cells. We have previously demonstrated that Bcl-2 is upregulated in tumor microvessels in patients with HNSCC. Here, we observed that Bcl-2 signaling induces expression of IL-6, CXCL8, and EGF, providing a mechanism for the upregulation of these cytokines in tumor-associated endothelial cells. This study expands the contribution of endothelial cells to the pathobiology of tumor cells. It unveils a new mechanism in which endothelial cells function as initiators of molecular crosstalks that enhance survival and migration of tumor cells.
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PMID:Cross talk initiated by endothelial cells enhances migration and inhibits anoikis of squamous cell carcinoma cells through STAT3/Akt/ERK signaling. 1948 47

Cardiac myofibroblasts (CMF) play a key role in infarct repair and scar formation following myocardial infarction (MI) and are also an important source of proinflammatory cytokines. We postulated that interleukin-1alpha (IL-1alpha), a potential early trigger of acute inflammation post-MI, could stimulate human CMF to express additional proinflammatory cytokines. Furthermore, we hypothesized that these effects may be modulated by the anti-inflammatory cytokine interleukin-10 (IL-10). Human CMF were cultured from atrial biopsies from multiple patients. Interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and cardiotrophin-1 (CT-1) mRNA expression and secretion were measured using quantitative real-time RT-PCR and enzyme-linked immunosorbent assay. IL-1alpha (0.001-10 ng/ml, 0-6 h) stimulated IL-1beta, TNF-alpha, and IL-6 mRNA expression with distinct temporal and concentration profiles, resulting in increased cytokine secretion. The response to IL-1alpha was much greater than with TNF-alpha. Neither IL-1alpha nor TNF-alpha treatment modulated CT-1 mRNA expression. Immunoblotting with phosphospecific antibodies revealed that IL-1alpha stimulated the extracellular signal-regulated kinase (ERK)-1/2, p38 mitogen-activated protein kinase (MAPK), c-Jun NH(2)-terminal kinase (JNK), phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt), and nuclear factor (NF)-kappaB signaling pathways. Pharmacological inhibitor studies indicated roles for PI 3-kinase/Akt and NF-kappaB pathways in mediating IL-1beta expression, and for NF-kappaB and p38 MAPK pathways in mediating TNF-alpha expression. IL-1alpha-induced IL-6 mRNA expression was reduced by p38 MAPK inhibition, but increased by ERK and JNK pathway inhibitors. IL-10 produced a consistent but modest reduction in IL-1alpha-induced IL-6 mRNA levels (not IL-1beta or TNF-alpha), but this was not reflected by reduced IL-6 protein secretion. In conclusion, IL-1alpha stimulates human CMF to express IL-1beta, TNF-alpha, and IL-6 via specific signaling pathways, responses that are unaffected by IL-10 exposure.
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PMID:Interleukin-1alpha stimulates proinflammatory cytokine expression in human cardiac myofibroblasts. 1964 52

Interleukin-6 (IL-6) is produced by neurons, astrocytes, and microglia, and elevated levels of IL-6 within the CNS have been documented in multiple neurological disorders including Alzheimer's disease, stroke, epilepsy, attention deficit disorder, cerebral palsy, and multiple sclerosis. Here, we sought to understand how IL-6 regulates microglial signal transduction and their immune properties. Using highly enriched cultures of neonatal murine microglia we show that IL-6 alone has direct effects on microglia as it activates STAT3 and extracellular signal-regulated kinase pathways in a time- and dose-dependent fashion and it enhances interferon-gamma (IFNgamma)-stimulated IL-12 secretion. However, other immune properties were only weakly modulated by IL-6 when administered without the soluble IL-6 receptor (sIL-6R). For instance, IFNgamma-induced expression of the co-stimulatory molecule, CD40 was dependent on sIL-6R administration. IL-6 with or without sIL-6R did not affect major histocompatability complex class II expression. In granulocyte-macrophage colony-stimulating factor (GMCSF)-induced dendritic cell-like microglia, IL-6/sIL-6R and IFNgamma stimulated an even greater increase in CD40 expression compared with primary microglia. Altogether, our results demonstrate that microglial responses to IL-6 are not simple in that the effects of IL-6 are context-dependent. In particular, the presence or absence of sIL-6R, IFNgamma or GMCSF will alter the type and amplitude of their response.
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PMID:Context-dependent IL-6 potentiation of interferon- gamma-induced IL-12 secretion and CD40 expression in murine microglia. 1971 53

The neuroprotective effects of purple sweet potato color (PSPC), which is natural anthocyanin food colors, have been investigated in mice treated with lipopolysaccharide (LPS). In behavioral tests, oral administration of PSPC could significantly reverse the impairment of motor and exploration behavior induced by LPS in the open field tasks, and also improve learning and memory ability in step-through tests. Western blot analysis indicated that PSPC significantly suppressed LPS-induced cyclooxygenase-2 (COX-2) and inducible nitric oxide synthases (iNOS) expression in mouse brain. PSPC also markedly decreased the overproduction of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) in LPS-stimulated mouse brain. Mechanistically, PSPC strongly inhibited LPS-induced phosphorylated extracellular signal-regulated kinase (ERK) and phosphorylated c-Jun N-terminal kinase (JNK) expression and nuclear factor kappa B (NF-kappaB) activation. Taken together, these data suggest that PSPC may be useful for mitigating inflammatory brain diseases by the inhibition of proinflammatory molecule production, at least in part, through blocking ERK, JNK and NF-kappaB signaling.
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PMID:Purple sweet potato color suppresses lipopolysaccharide-induced acute inflammatory response in mouse brain. 1994 23

The skin lesions of inflammatory skin diseases (e.g., atopic dermatitis or psoriasis) accompany infiltration of inflammatory cells like macrophages, where abnormal sensory innervations and elevation of nerve growth factor (NGF) level are observed. It is thought that increased NGF mediates the abnormal innervations and this may cause the hypersensitivity of the skin. However, the mechanism of this increased NGF production in the skin is still unknown. Here, we show that tumor necrosis factor (TNF)-alpha, but not interferon-gamma or interleukin-6, enhanced the NGF production in human keratinocytes. The enhanced NGF production was abolished by both Raf-1 kinase and MEK inhibitors, whereas specific inhibitors of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase did not. The extracellular signal-regulated kinase (ERK) phosphorylation and expression of NGF mRNA were accelerated by TNF-alpha treatment. Furthermore, serum was necessary for the NGF production and epidermal growth factor could substitute for serum in the effect on NGF secretion. These results indicate that TNF-alpha enhances NGF production via the Raf-1 / MEK / ERK pathway in human keratinocytes, suggesting that regulating TNF-alpha is a therapeutic target to control NGF production and subsequent sensory innervations.
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PMID:Inflammatory cytokine tumor necrosis factor-alpha enhances nerve growth factor production in human keratinocytes, HaCaT cells. 1994 4

Sodium arsenite (NaAs)-induced autophagic cell death (ACD) of a mouse renal tubular epithelial cell line (mProx24), which expresses enhanced levels of interleukin-6 (IL-6), was reduced by the suppression of autophagy by 3-methyladenine or Atg7 knockdown. The inhibition of the IL-6/signal transducer and activator of transcription 3 (STAT3) signal pathway by anti-IL-6 antibody or a Jak2 inhibitor (AG490) exaggerated ACD of mProx24 cells after NaAs challenge, attenuating STAT3 activation and reciprocally enhancing extracellular signal-regulated kinase (ERK) phosphorylation. In contrast, an ERK inhibitor, PD98059, reduced NaAs-induced ACD in mProx24 cells. Subcutaneous injection of NaAs (12.5 mg/kg) into BALB/c (wild-type) mice enhanced intrarenal expression of IL-6, mainly produced by tubular cells, and caused severe renal injury characterized by hemorrhages, acute tubular necrosis, cast formation, and brush border disappearance, with increases in serum urea nitrogen (blood urea nitrogen) and creatinine levels. In addition, IL-6-deficient (IL-6(-/-)) mice exhibited exaggerated histopathological changes with higher blood urea nitrogen and creatinine levels. Moreover, in IL-6(-/-) mice treated with NaAs, ACD in renal tubular cells was significantly augmented, along with diminished STAT3 activation and reciprocal enhancement of ERK signaling, compared with wild-type mice. Finally, the administration of exogenous IL-6 into wild-type mice significantly reduced NaAs-induced ACD along with diminished ERK activation and eventually alleviated acute renal dysfunction. Thus, IL-6/STAT3 signal pathway could inhibit ERK activation, a crucial step for ACD, eventually attenuating NaAs-induced renal dysfunction.
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PMID:The absence of interleukin-6 enhanced arsenite-induced renal injury by promoting autophagy of tubular epithelial cells with aberrant extracellular signal-regulated kinase activation. 2000 37

Interleukin-6 (IL-6) is a growth factor for human myeloma cells. We have recently found that in myeloma cells the activation of both signal transducer and activator of transcription (STAT) 3 and extracellular signal-regulated kinase (ERK) 1/2 is not sufficient for the IL-6-induced proliferation, which further requires the activation of the src family kinases, such as Lyn. Here we showed that the Lyn-overexpressed myeloma cell lines had the higher proliferative rate with IL-6 and the enhanced activation of the phosphatidylinositol (PI) 3-kinase and Akt. The IL-6-induced phosphorylation of STAT3 and ERK1/2 was not up-regulated in the Lyn-overexpressed cells, indicating that the Lyn-PI 3-kinase-Akt pathway is independent of these pathways. The PI 3-kinase was co-precipitated with Lyn in the Lyn-overexpressed cells of which proliferation with IL-6 was abrogated by the specific inhibitors for PI 3-kinase or Akt, suggesting that the activation of the PI 3-kinase-Akt pathway associated with Lyn is indeed related to the concomitant augmentation of myeloma cell growth. Furthermore, the decreased expression of p53 and p21(Cip1) proteins was observed in the Lyn-overexpressed cells, implicating a possible downstream target of Akt. This study identifies a novel IL-6-mediated signaling pathway that certainly plays a role in the proliferation of myeloma cells and this novel mechanism of MM tumor cell growth associated with Lyn would eventually contribute to the development of MM treatment.
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PMID:A novel signaling pathway associated with Lyn, PI 3-kinase and Akt supports the proliferation of myeloma cells. 2007 16


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