Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin, the adipocyte-secreted hormone that centrally regulates weight control, is known to function as an immunomodulatory regulator. We investigated the signaling pathway involved in IL-6 production caused by leptin in microglia. Microglia expressed the long (OBRl) and short (OBRs) isoforms of the leptin receptor. Leptin caused concentration- and time-dependent increases in IL-6 production. Leptin-mediated IL-6 production was attenuated by OBRl receptor antisense oligonucleotide, PI3K inhibitor (Ly294002 and wortmannin), Akt inhibitor (1L-6-hydroxymethyl-chiro-inositol-2-((R)-2-O-methyl-3-O-octadecylcarbonate)), NF-kappaB inhibitor (pyrrolidine dithiocarbamate), IkappaB protease inhibitor (L-1-tosylamido-2-phenylenylethyl chloromethyl ketone), IkappaBalpha phosphorylation inhibitor (Bay 117082), or NF-kappaB inhibitor peptide. Transfection with insulin receptor substrate (IRS)-1 small-interference RNA or the dominant-negative mutant of p85 and Akt also inhibited the potentiating action of leptin. Stimulation of microglia with leptin activated IkappaB kinase alpha/IkappaB kinase beta, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation at Ser(276), p65 and p50 translocation from the cytosol to the nucleus, and kappaB-luciferase activity. Leptin-mediated an increase of IkappaB kinase alpha/IkappaB kinase beta activity, kappaB-luciferase activity, and p65 and p50 binding to the NF-kappaB element was inhibited by wortmannin, Akt inhibitor, and IRS-1 small-interference RNA. The binding of p65 and p50 to the NF-kappaB elements, as well as the recruitment of p300 and the enhancement of histone H3 and H4 acetylation on the IL-6 promoter was enhanced by leptin. Our results suggest that leptin increased IL-6 production in microglia via the leptin receptor/IRS-1/PI3K/Akt/NF-kappaB and p300 signaling pathway.
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PMID:Leptin-induced IL-6 production is mediated by leptin receptor, insulin receptor substrate-1, phosphatidylinositol 3-kinase, Akt, NF-kappaB, and p300 pathway in microglia. 1761 22

Transforming growth factor-beta1 (TGF-beta1) plays an essential role in tumor progression and metastasis. Integrins are the major adhesive molecules in mammalian cells. Here we found that TGF-beta1 increased the migration and cell surface expression of alphavbeta3 integrin in human chondrosarcoma cells (JJ012 cells). Phosphatidylinositol 3-kinase inhibitor (PI3K; Ly294002) or Akt inhibitor inhibited the TGF-beta1-induced increase the migration of chondrosarcoma cells. TGF-beta1 stimulation increased the phosphorylation of p85 subunit of PI3K, and serine 473 of Akt. In addition, treatment of JJ102 cells with NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) inhibited TGF-beta1-induced cells migration and integrins expression. Treatment of JJ012 cells with TGF-beta1-induced IkappaB kinase alpha/beta (IKKalpha/beta) phosphorylation, IkappaBalpha phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. The TGF-beta1-mediated increases in IKKalpha/beta phosphorylation and p65 Ser(536) phosphorylation were inhibited by Ly294002 and Akt inhibitor. Cotransfection with p85 and Akt mutants also reduced the TGF-beta1-induced kappaB-luciferase activity. Taken together, these results suggest that the TGF-beta1 acts through PI3K/Akt, which in turn activates IKKalpha/beta and NF-kappaB, resulting in the activations of alphavbeta3 integrins and contributing the migration of chondrosarcoma cells.
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PMID:TGF-beta1 increases motility and alphavbeta3 integrin up-regulation via PI3K, Akt and NF-kappaB-dependent pathway in human chondrosarcoma cells. 1819 Nov 7

Leptin, the adipocyte-secreted hormone that centrally regulates weight control, is known to function as an immunomodulatory regulator. We investigated the signaling pathway involved in IL-8 production caused by leptin in both rheumatoid arthritis synovial fibroblasts (RASF) and osteoarthritis synovial fibroblasts (OASF). RASF and OASF expressed the long (OBRl) and short (OBRs) isoforms of the leptin receptor. Leptin caused concentration- and time-dependent increases in IL-8 production. Leptin-mediated IL-8 production was attenuated by OBRl receptor antisense oligonucleotide, JAK2 inhibitor or STAT3 small interference RNA (siRNA). Transfection with insulin receptor substrate (IRS)-1 siRNA or dominant-negative mutant of p85 and Akt or pretreatment with phosphatidylinositol 3-kinase inhibitor (Ly294002 and wortmannin), Akt inhibitor, NF-kappaB inhibitor (PDTC) and NF-kappaB inhibitor peptide also inhibited the potentiating action of leptin. Stimulation of RASF with leptin activated IkappaB kinase alpha/beta (IKK alpha/beta), p65 phosphorylation at Ser(276), p65 translocation from the cytosol to the nucleus, and kappaB-luciferase activity. Moreover, pretreatment with p300 inhibitor (curcumin) also blocked IL-8 expression. The binding of p65 to the NF-kappaB elements, as well as the recruitment of p300 and the enhancement of histone H3 acetylation on the IL-8 promoter was enhanced by leptin, which was inhibited by wortmannin, Akt inhibitor or IRS-1 siRNA. These results suggest that leptin increased IL-8 production in synovial fibroblast via the OBRl/JAK2/STAT3 pathway, as well as the activation of IRS1/PI3K/Akt/NF-kappaB-dependent pathway and the subsequent recruitment of p300.
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PMID:Leptin induces IL-8 expression via leptin receptor, IRS-1, PI3K, Akt cascade and promotion of NF-kappaB/p300 binding in human synovial fibroblasts. 1850 60

Bone morphogenetic protein-2 (BMP-2), a member of transforming growth factor-beta superfamily, plays a crucial role in migration and metastasis of human cancer cells. Integrins are the major adhesive molecules in mammalian cells. Here we found that BMP-2 directed the migration and increased cell surface and mRNA expression of beta1 integrin in human chondrosarcoma cancer cells (JJ012). Pretreated of JJ012 cells with phosphatidylinositol 3-kinase inhibitor (PI3K; Ly294002) or Akt inhibitor inhibited the BMP-2-mediated migration and integrin expression. BMP-2 increased the phosphorylation of p85 subunit of PI3K and serine 473 of Akt. In addition, NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) also inhibited BMP-2-mediated cells migration and integrin upregulation. Stimulation of JJ012 cells with BMP-2 induced IkappaB kinase (IKKalpha/beta) phosphorylation, IkappaB phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. Furthermore, the BMP-2-mediated increasing of IKKalpha/beta phosphorylation, IkappaB phosphorylation, and p65 Ser(536) phosphorylation were inhibited by Ly294002 and Akt inhibitor. Co-transfection with p85 and Akt mutants also reduced the BMP-2-induced kappaB-luciferase activity. Taken together, these results suggest that the BMP-2 acts through PI3K/Akt, which in turn activates IKKalpha/beta and NF-kappaB, resulting in the activations of beta1 integrin and contributing the migration of human chondrosarcoma cells.
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PMID:BMP-2 increases migration of human chondrosarcoma cells via PI3K/Akt pathway. 1872 Apr 10

Advanced glycation end products (AGEs) could be implicated in insulin resistance. However, the molecular mechanisms underlying this are not fully understood. Since pigment epithelium-derived factor (PEDF) blocks the AGE-signaling pathways, we examined here whether and how PEDF improves insulin resistance in AGE-exposed hepatoma cells, Hep3B cells. Proteins were extracted from Hep3B cells, immunoprecipitated with or without insulin receptor substrate-1 (IRS-1) antibodies, and subjected to Western blot analysis. Glycogen synthesis was measured using [ (14)C]-d-glucose. AGE induced Rac-1 activation and increased phosphorylation of IRS-1 at serine-307 residues, JNK, c-JUN, and IkappaB kinase in association with decreased IkappaB levels in Hep3B cells. PEDF or overexpression of dominant negative Rac-1 blocked these effects of AGE on Hep3B cells. Further, AGEs decreased tyrosine phosphorylation of IRS-1, and subsequently reduced the association of p85 subunit of phosphatidylinositol 3-kinase with IRS-1 and glycogen synthesis in insulin-exposed Hep3B cells, all of which were inhibited by PEDF. Our present study suggests that PEDF could improve the AGE-elicited insulin resistance in Hep3B cells by inhibiting JNK- and IkappaB kinase-dependent serine phosphorylation of IRS-1 via suppression of Rac-1 activation. PEDF may play a protective role against hepatic insulin resistance in diabetes.
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PMID:Pigment epithelium-derived factor (PEDF) ameliorates advanced glycation end product (AGE)-induced hepatic insulin resistance in vitro by suppressing Rac-1 activation. 1879 73

Tumor malignancy is associated with several features such as proliferation ability and frequency of metastasis. Osteopontin (OPN), which is abundantly expressed in bone matrix, is involved in cell adhesion, migration, invasion and cell proliferation via interaction with its receptor, alphavbeta3 integrin. However, the effect of OPN on migration activity in human lung cancer cells is mostly unknown. Here we found that OPN increased the migration via activation of alphavbeta3 integrin in human lung cancer cells (A549 cells). Phosphatidylinositol 3-kinase inhibitor (PI3K; Ly294002), Akt inhibitor or ERK inhibitor (PD98059) inhibited the OPN-induced increase in the migration of lung cancer cells. OPN stimulation increased the phosphorylation of focal adhesion kinase (FAK), p85 subunit of PI3K, serine 473 of Akt and ERK. In addition, treatment of A549 cells with NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) inhibited OPN-induced migration of lung cancer cells. Stimulation of A549 cells with OPN also induced IkappaB kinase alpha/beta (IKK alpha/beta) phosphorylation, IkappaBalpha phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. The OPN-mediated increases in IKK alpha/beta, IkappaBalpha and p65 Ser(536) phosphorylation were inhibited by Ly294002, Akt inhibitor and PD98059. Co-transfection with FAK, p85, Akt and ERK mutants also reduced the OPN-induced kappaB-luciferase activity. Taken together, these results suggest that OPN acts through alphavbeta3 integrin, which in turn activates the FAK, PI3K, Akt, ERK and NF-kappaB pathways, contributing to the migration of lung cancer cells.
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PMID:Osteopontin increases lung cancer cells migration via activation of the alphavbeta3 integrin/FAK/Akt and NF-kappaB-dependent pathway. 1899 13

CCL5 (previously called RANTES) is in the CC-chemokine family and plays a crucial role in the migration and metastasis of human cancer cells. Besides, integrins are the major adhesive molecules in mammalian cells. Here we found CCL5 increased the migration and cell surface expression of alphavbeta3 integrin in human lung cancer cells (A549 cells). CCL5 stimulation increased phosphorylation of the p85alpha subunit of phosphatidylinositol 3-kinase (PI3K) and serine 473 of Akt. Also, we found that PI3K inhibitor (Ly294002) or Akt inhibitor suppressed CCL5-induced migration activities and integrin expression of A549 cells. Transfection of cells with p85 or Akt mutant also reduced CCL5-mediated cancer migration. In addition, treatment of A549 cells with CCL5 induced IkappaB kinase alpha/beta (IKK alpha/beta) phosphorylation, IkappaB phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. Furthermore, the CCL5-mediated increases in p65 Ser(536) phosphorylation were inhibited by Ly294002 and Akt inhibitor. Taken together, our results suggest that CCL5 acts through PI3K/Akt, which in turn activates IKKalpha/beta and NF-kappaB, resulting in the activation of alphavbeta3 integrin and contributing to the migration of human lung cancer cells.
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PMID:CCL5 increases lung cancer migration via PI3K, Akt and NF-kappaB pathways. 1907 47

Ginsenoside Rp1 (G-Rp1) is a ginseng saponin derivative with chemopreventive and anti-cancer activities. In this study, we examined the regulatory activity of G-Rp1 on the production of interleukin (IL)-1beta, a pro-inflammatory cytokine managing acute or chronic inflammatory diseases such as septic shock and rheumatoid arthritis, from lipopolysaccharide (LPS)-treated macrophage-like RAW264.7 cells. G-Rp1 dose-dependently inhibited IL-1beta production from LPS-treated RAW264.7 cells without altering cell viability. This compound suppressed both mRNA and protein levels of IL-1beta. In particular, this compound was found to down-regulate phosphorylation of the inhibitor of kappaB (IkappaB) kinase (IKK)/IkappaBalpha, and consequent activation of NF-kappaB, but not the activation of its upstream signaling enzymes such as mitogen-activated protein kinases (MAPK) and p85, a regulatory subunit of phosphoinositide 3-kinase (PI3K). Therefore, these results suggest that G-Rp1 may act as an inhibitor of IL-1beta production by inhibiting the NF-kappaB pathway.
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PMID:Ginsenoside Rp1, a ginsenoside derivative, blocks lipopolysaccharide-induced interleukin-1beta production via suppression of the NF-kappaB pathway. 1914 54

Stromal cell-derived factor-1 (SDF-1), also known as CXCL12, and its receptor CXC chemokine receptor 4 (CXCR4) express in various kinds of cells in central nervous system. The SDF-1/CXCR4 signaling pathway is regulated by diverse biological effects. SDF-1 is up-regulated in the ischemic penumbra following stroke and has been known to be associated with the homing of bone marrow cells to injury. However, the effect of SDF-1alpha/CXCR4 on cytokine production in microglia is mostly unknown. Here, we demonstrated that SDF-1alpha enhanced IL-6 production in both primary cultured microglia and BV-2 microglia. We further investigated the signaling pathway involved in IL-6 production stimulated by SDF-1alpha in microglia. SDF-1alpha increased IL-6 production in both protein and mRNA levels. These effects were attenuated by ERK, phosphatidylinositol 3-kinase (PI3K), NF-kappaB inhibitors, and IkappaB protease inhibitor. Stimulation of microglia with SDF-1alpha also increased Akt and ERK1/2 phosphorylation. In addition, SDF-1alpha treatment also increased IkappaB kinase alpha/beta (IKK alpha/beta) phosphorylation, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation at Ser(276), translocation of p65 and p50 from cytosol to nucleus and kappaB-luciferase activity. Moreover, SDF-1alpha-mediated increase of kappaB-luciferase activity was inhibited by pre-transfection of DN-p85, DN-Akt or DN-ERK2. Increase of IKK alpha/beta phosphorylation and binding of p65 and p50 to the NF-kappaB element were both antagonized by PI3K and ERK inhibitors. Our results demonstrate a mechanism linking SDF-1alpha and IL-6, and provide additional support for the notion that SDF-1alpha plays a regulatory role in microglia activation.
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PMID:SDF-1alpha up-regulates interleukin-6 through CXCR4, PI3K/Akt, ERK, and NF-kappaB-dependent pathway in microglia. 1928 61

In this study, we investigated the signaling pathways involved in inflammatory production caused by peptidoglycan (PGN), a cell wall component of the gram-positive bacterium, in BV-2 microglia. PGN caused a concentration- and time-dependent increase in inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA and protein levels. In addition, PGN also induced IL-1 beta, TNF-alpha and IL-6 mRNA up-regulation in a concentration-dependent manner. Moreover, PGN also increased Toll-like receptor 2 (TLR2) expression in BV-2 microglia. Administration of TLR2 neutralizing antibody effectively inhibited PGN-induced iNOS and COX-2 expression. On the other hand, PGN-induced iNOS and COX-2 up-regulation were attenuated by PI3-kinase inhibitors (LY294002 and wortmannin), and an AKT inhibitor. Treatment of BV-2 microglia with PGN caused a time-dependent activation of PI3-kinase (p85) and AKT. PGN-induced PI3-kinase/AKT activation, iNOS and COX-2 expression were also inhibited by MyD88 inhibitory peptide. Treatment of cells with NF-kappaB inhibitor (pyrrolidine dithiocarbamate), I kappaB alpha phosphorylation inhibitor (Bay 117082), or I kappaB protease inhibitor (l-1-tosylamido-2-phenylethyl chloromethyl ketone) inhibited PGN-induced iNOS and COX-2 expression. Furthermore, stimulation of cells with PGN also activated IKK alpha/beta, I kappaB alpha phosphorylation, I kappaB alpha degradation, p65 phosphorylation at Ser(536), and increased kappaB-luciferase activity. PGN-induced IKK alpha/beta phosphorylation, I kappaB alpha phosphorylation, and I kappaB alpha degradation were further inhibited by pre-treatment with PI3-kinase inhibitors. Moreover, PGN-mediated increase of kappaB-luciferase activity was also inhibited by pre-transfection with dominant-negative mutants of p85, AKT, IKK alpha or IKK beta. Our data demonstrate that PGN-induced iNOS, COX-2 and proinflammatory cytokine expression was mediated through the TLR2/MyD88/PI3-kinase/AKT pathway, which in turn initiates IKK alpha/beta and NF-kappaB activation in BV-2 microglia.
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PMID:Peptidoglycan enhances proinflammatory cytokine expression through the TLR2 receptor, MyD88, phosphatidylinositol 3-kinase/AKT and NF-kappaB pathways in BV-2 microglia. 2045 69


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