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)

Heat shock (HS) treatment has been previously shown to suppress the IkappaB/nuclear factor-kappaB (NF-kappaB) cascade by denaturing, and thus inactivating IkappaB kinase (IKK). HS is characterized by the induction of a group of heat shock proteins (HSPs). However, their role in the HS-induced suppression of the IkappaB/NF-kappaB cascade is unclear. Adenovirus-mediated HSP70 overexpression was found not to suppress the TNF-alpha-induced activation of the IkappaB/NF-kappaB pathway, thus suggesting that HSP70 is unlikely to suppress this pathway. When TNF-alpha-induced activation of the IkappaB/NF-kappaB pathway was regained 24 h after HS, HSP70 was found to be highly up-regulated. Moreover, blocking HSP70 induction delayed TNF-alpha-induced IkappaBalpha degradation and the resolubilization of IKK. In addition, HSP70 associated physically with IKK, suggesting that HSP70 is involved in the recovery process via molecular chaperone effect. Adenovirus-mediated HSP70 overexpression prior to HS blocked the IkappaBalpha stabilizing effect of HS by suppressing IKK insolubilization. Moreover, the up-regulation of endogenous HSP70 by preheating, suppressed this subsequent HS-induced IKK insolubilization, and this effect was abrogated by blocking HSP70 induction. These findings indicate that HSP70 accumulates during HS and negatively regulates the HS-induced suppression of the IkappaB/NF-kappaB cascade by facilitating the renaturation of IKK and blocking its further denaturation.
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PMID:Heat shock protein 70 negatively regulates the heat-shock-induced suppression of the IkappaB/NF-kappaB cascade by facilitating IkappaB kinase renaturation and blocking its further denaturation. 1592 46

Escherichia coli is associated with inflammation in the brain. To investigate whether astrocytes are involved in E. coil-induced inflammation, we assessed the levels of expression of proinflammatory mediators produced by E. coli-infected astrocytes. E. coli infection in primary human astrocytes and cell lines increased expression of the CXC chemokine IL-8/GRO-alpha, the CC chemokine MCP-1, TNF-alpha, and iNOS. E. coli infection activated p65/p50 heterodimeric NF-kappaB and concurrently decreased the signals of IkappaBalpha. Blocking the NF-kappaB signals by IkappaBalpha-superrepressor-containing retrovirus or antisense p50 oligonucleotide transfection resulted in down-regulation of expression of the proinflammatory mediators. Furthermore, superrepressors of IkappaBalpha, IkappaB kinase (IKK) or NF-kappaB inducing kinase (NIK) inhibited the up-regulated expression of the downstream target genes of NF-kappaB such as IL-8 and MCP-1, and superrepressors of TNF receptor-associated factor (TRAF)2 and TRAF5 also inhibited expression of the E. coli-induced target genes of NF-kappaB. These results indicate that proinflammatory mediators such as the CXC chemokine IL-8/GRO-alpha, the CC chemokine MCP-1, TNF-alpha, and iNOS can be expressed in E. coli-infected astrocytes via an NF-kappaB pathway, suggesting that these mediators may contribute to inflammation in the brain, including infiltration of inflammatory cells.
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PMID:Induction of proinflammatory mediators requires activation of the TRAF, NIK, IKK and NF-kappaB signal transduction pathway in astrocytes infected with Escherichia coli. 1593 6

The inhibitor of NF-kappaB (I-kappaB) kinase (IKK) complex consists of 3 subunits, IKK1, IKK2, and NF-kappaB essential modulator (NEMO), and is involved in the activation of NF-kappaB by various stimuli. IKK2 or NEMO constitutive knockout mice die during embryogenesis as a result of massive hepatic apoptosis. Therefore, we examined the role of IKK2 in TNF-induced apoptosis and ischemia/reperfusion (I/R) injury in the liver by using conditional knockout mice. Hepatocyte-specific ablation of IKK2 did not lead to impaired activation of NF-kappaB or increased apoptosis after TNF-alpha stimulation whereas conditional NEMO knockout resulted in complete block of NF-kappaB activation and massive hepatocyte apoptosis. In a model of partial hepatic I/R injury, mice lacking IKK2 in hepatocytes displayed significantly reduced liver necrosis and inflammation than wild-type mice. AS602868, a novel chemical inhibitor of IKK2, protected mice from liver injury due to I/R without sensitizing them toward TNF-induced apoptosis and could therefore emerge as a new pharmacological therapy for liver resection, hemorrhagic shock, or transplantation surgery.
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PMID:Activation and function of hepatocyte NF-kappaB in postischemic liver injury. 1577 10

Fas-associated death-domain protein (FADD) is an adaptor molecule that links death receptors to caspase-8 in many cell types including cardiomyocytes (CMs). Although FADD has previously been reported to play an important role in CM apoptosis, the effect of FADD on CM NF-kappaB signaling, which is a proinflammatory pathway, has not been delineated. To investigate the role of FADD in CM NF-kappaB activation, we utilized adenoviral gene transfer of wild-type FADD and a truncation mutant that lacks the death-effector domain (FADD-DED) in rat CMs in vitro TNF-alpha activated NF-kappaB in CMs as demonstrated by phosphorylation and degradation of inhibitory-kappaB (IkappaB)-alpha-enhanced nuclear p65 and NF-kappaB DNA-binding activity as well as increased mRNA for the NF-kappaB-dependent adhesion molecule VCAM-1 (19 +/- 4.1-fold) as measured by quantitative RT-PCR. Gene transfer of FADD inhibited TNF-alpha-induced IkappaB-alpha phosphorylation, decreased p65 nuclear translocation and NF-kappaB DNA-binding activity, and reduced VCAM-1 transcript levels by 53-65%. Interestingly, FADD-DED exhibited a similar but weaker inhibitory effect on NF-kappaB activation. The effects of FADD on NF-kappaB were cell-type specific. FADD expression also inhibited TNF-alpha-mediated NF-kappaB activation in human endothelial cells but not in rat pulmonary artery smooth muscle cells. In contrast, FADD expression actually activated NF-kappaB in human embryonic kidney (HEK)-293 cells. In CMs, FADD inhibited NF-kappaB activation as well as phosphorylation of IkappaB-alpha and IkappaB kinase (IKK)-beta in response to cytokine stimulation or expression of the upstream kinases NF-kappaB-inducing kinase and IKK-beta. These data demonstrate that FADD inhibits NF-kappaB activation in CMs, and this inhibition likely occurs at the level of phosphorylation and activation of IKK-beta.
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PMID:Fas-associated death-domain protein inhibits TNF-alpha mediated NF-kappaB activation in cardiomyocytes. 1598 38

The efficacy of 18beta-glycyrrhetinic acid (GRA), a pentacyclic triterpene belonging to the beta-amyrin series of plant origin, was evaluated in experimental visceral leishmaniasis. GRA is reported to have antitumor and immunoregulatory activities, which may be attributable in part to the induction of NO. Indeed, an 11-fold increase in NO production was observed with 20 microM GRA in mouse peritoneal macrophages infected with Leishmania donovani promastigotes. In addition to having appreciable inhibitory effects on amastigote multiplication within macrophages (IC(50), 4.6 microg/ml), complete elimination of liver and spleen parasite burden was achieved by GRA at a dose of 50 mg/kg/day, given three times, 5 days apart, in a 45-day mouse model of visceral leishmaniasis. GRA treatment resulted in reduced levels of IL-10 and IL-4, but increased levels of IL-12, IFN-gamma, TNF-alpha, and inducible NO synthase, reflecting a switch of CD4(+) differentiation from Th2 to Th1. This treatment is likely to activate immunity, thereby imparting resistance to reinfection. GRA induced NF-kappaB migration into the nucleus of parasite-infected cells and caused a diminishing presence of IkappaB in the cytoplasm. The lower level of cytoplasmic IkappaBalpha in GRA-treated cells resulted from increased phosphorylation of IkappaBalpha and higher activity of IkappaB kinase (IKK). Additional experiments demonstrated that GRA does not directly affect IKK activity. These results suggest that GRA exerts its effects at some level upstream of IKK in the signaling pathway and induces the production of proinflammatory mediators through a mechanism that, at least in part, involves induction of NF-kappaB activation.
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PMID:18 Beta-glycyrrhetinic acid triggers curative Th1 response and nitric oxide up-regulation in experimental visceral leishmaniasis associated with the activation of NF-kappa B. 1600 18

The transcription factor nuclear factor-kappa B (NF-kappaB) subunit p65 is phosphorylated by IkappaB kinase (IKK) at S536 in transactivation domain (TAD) 1. In this study, we investigate the presence of IKK sites in TAD2 of p65. Recombinant IKKbeta, but not IKKalpha, phosphorylated a GST-p65 substrate in which TAD1 was deleted. Mutational analysis revealed S468 as the only IKK site in TAD2. S468 phosphorylation occurred rapidly after TNF-alpha and IL-1beta in T cell, B cell, cervix carcinoma, hepatoma, breast cancer, and astrocytoma lines and in primary hepatic stellate cells as well as peripheral blood mononuclear cells. S468-phosphorylated p65 coimmunoprecipitated with IkappaBalpha, indicating that p65 is phosphorylated while bound to IkappaBalpha. Dominant negative IKKbeta or pharmacological IKK inhibition blocked S468 phosphorylation after TNF-alpha or IL-1beta, whereas dominant negative IKKalpha or inhibitors of MEK, p38, JNK, PI-3 kinase, or GSK-3 had no effect. p65S468A-reconstituted p65-/- mouse embryonic fibroblasts (MEFs) showed a small, but significant, elevation of NF-kappaB-driven luciferase activity and RANTES mRNA levels after TNF-alpha and IL-1beta in comparison to wtp65-reconstituted MEFs. p65 nuclear translocation was not altered in p65S468A-expressing MEFs. In conclusion, our results indicate that 1) IKKbeta phosphorylates multiple p65 sites, 2) IKKbeta phosphorylates p65 in an IkappaB-p65 complex, and 3) S468 phosphorylation slightly reduces TNF-alpha- and IL-1beta-induced NF-kappaB activation.
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PMID:IKKbeta phosphorylates p65 at S468 in transactivaton domain 2. 1604 71

Statins have been linked to a wide range of vascular benefits, many of them are likely to be due to attenuation of chronic vascular inflammation. Nuclear factor kappaB (NF-kappaB) is one of the key regulators of transcription of a variety of genes involved in immune and inflammatory responses. Therefore, we investigated the effect of statins on TNF-alpha-induced NF-kappaB signaling in human endothelial cells (EC). ECs were pre-incubated for 16 h with cerivastatin (10(-9) to 10(-7) M) or vehicle in the presence or absence of mevalonate, followed by stimulation with 20 ng/ml TNF-alpha. Statin-treatment prevented TNF-alpha-induced NF-kappaB binding activity, nuclear translocation of the NF-kappaB p65 subunit, as well as NF-kappaB controlled tissue factor (TF) gene transcription in cultured EC. IkappaBalpha phosphorylation and IkappaBalpha degradation, however, still occurred in statin-treated cells. TNF-alpha also activated phosphatidylinositol (PI)3-kinase, as reflected by phosphorylation of Akt. Statin treatment of cells abrogated TNF-alpha-induced Akt phosphorylation and p65 nuclear translocation. As observed with statins, inhibition of PI3-kinase activity by Ly294002 also blocked TNF-alpha-induced p65 translocation, but did not prevent IkappaBalpha phosphorylation nor IkappaBalpha degradation. These studies demonstrate that TNF-alpha-induced NF-kappaB activation is abrogated by statin treatment in HUVEC independently of the classical IKK-pathway but via inhibition of PI3-kinase/Akt signaling.
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PMID:Statins prevent NF-kappaB transactivation independently of the IKK-pathway in human endothelial cells. 1605 Dec 51

IKK-i and TBK1 were recently identified as IKK-related kinases that are activated by toll-like receptors TLR3 and TLR4. These kinases were identified as essential components of the virus-activated as well as LPS-MyD88 independent kinase complex that phosphorylates IRF3 and results in the production of cytokines involved in innate immunity. Both IKK-i and TBK1 have also been implicated in the activation of the NFkappaB pathway but the precise mechanism is not clear. Although the literature to date suggests that IKK-i and TBK1 play redundant roles in TLR3 and TLR4 signaling, recent data suggest that there may be subtle differences in the signaling pathways affected by these kinases. We have generated tetracycline-inducible stable cell lines that express a wild type or kinase-inactive mutant form of IKK-i. Our data suggest that expression of IKK-i can activate both NFkappaB and IRF3, leading to the production of several cytokines including interferon beta. IKK-i most likely acts upstream of IKK2 to activate NFkappaB in these cells since expression of the kinase-inactive version of IKK-i did not inhibit TNFalpha mediated production of inflammatory cytokines. The data suggest that IKK-i is not involved in TNF-alpha mediated signaling but instead could likely play a role in activating IKK2 downstream of Toll-like receptor signaling. We also identified STAT1, Tyk2, and JAK1 as secondary mediators of IKK-i signaling as a result of interferon beta production in these cells.
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PMID:IKK-i signals through IRF3 and NFkappaB to mediate the production of inflammatory cytokines. 1619 37

Unveiling of endothelial nuclear factor-kappaB (NF-kappaB) activation is pivotal for understanding the inflammatory reaction and the pathogenesis of inflammatory vascular diseases. We here report the novel function of extracellular signal-related kinase (ERK) in controlling endothelial NF-kappaB activation and inflammatory responses. In human endothelial cells, vascular endothelial growth factor (VEGF) induced NF-kappaB-dependent transcription of cell adhesion molecules (CAMs) and monocyte adhesion. These effects were prominently enhanced by either pretreatment with the MEK inhibitors, PD98059 and U0126 or overexpression of a dominant negative form of MEK, but blocked by a wild type ERK. Consistently, inhibition of ERK significantly increased IkappaB kinase (IKK) activity, IkappaBalpha phosphorylation, and nuclear translocation of NF-kappaB induced by VEGF, whereas overexpression of ERK resulted in the loss of these responses to VEGF. Using two PKC inhibitors has demonstrated that VEGF concomitantly stimulates IKK and its negative regulatory signal ERK through PKC that lies downstream of KDR/Flk-1. Strikingly, elevation of ERK in endothelial cells markedly inhibited CAM expression and NF-kappaB activation as well as monocyte adhesion induced by IL-1beta and TNF-alpha. The data collectively suggest that ERK serves as an anti-inflammatory signal that suppresses expression of NF-kappaB-dependent inflammatory genes by inhibiting IKK activity in endothelial cells. Measuring the existence of ERK activity in vascular endothelial cells may be useful for predicting the feasibility and potency of inflammatory reactions in the vasculature.
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PMID:ERK is an anti-inflammatory signal that suppresses expression of NF-kappaB-dependent inflammatory genes by inhibiting IKK activity in endothelial cells. 1624 16

TGF-beta-activated kinase 1 (TAK1), a member of the MAPKKK family, is thought to be a key modulator of the inducible transcription factors NF-kappaB and AP-1 and, therefore, plays a crucial role in regulating the genes that mediate inflammation. Although in vitro biochemical studies have revealed the existence of a TAK1 complex, which includes TAK1 and the adapter proteins TAB1 and TAB2, it remains unclear which members of this complex are essential for signaling. To analyze the function of TAK1 in vivo, we have deleted the Tak1 gene in mice, with the resulting phenotype being early embryonic lethality. Using embryonic fibroblasts lacking TAK1, TAB1, or TAB2, we have found that TNFR1, IL-1R, TLR3, and TLR4-mediated NF-kappaB and AP-1 activation are severely impaired in Tak1(m/m) cells, but they are normal in Tab1(-/-) and Tab2(-/-) cells. In addition, Tak1(m/m) cells are highly sensitive to TNF-induced apoptosis. TAK1 mediates IKK activation in TNF-alpha and IL-1 signaling pathways, where it functions downstream of RIP1-TRAF2 and MyD88-IRAK1-TRAF6, respectively. However, TAK1 is not required for NF-kappaB activation through the alternative pathway following LT-beta signaling. In the TGF-beta signaling pathway, TAK1 deletion leads to impaired NF-kappaB and c-Jun N-terminal kinase (JNK) activation without impacting Smad2 activation or TGF-beta-induced gene expression. Therefore, our studies suggests that TAK1 acts as an upstream activating kinase for IKKbeta and JNK, but not IKKalpha, revealing an unexpectedly specific role of TAK1 in inflammatory signaling pathways.
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PMID:TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. 1626 Apr 93


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