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)

Acacetin (5,7-dihydroxy-4'-methoxyflavone), a flavonoid compound, has anti-peroxidative and anti-inflammatory effects. In this study, we investigated the inhibitory effects of acacetin and a related compound, wogonin, on the induction of NO synthase (NOS) and COX-2 in RAW 264.7 cells activated with lipopolysaccharide (LPS). Acacetin markedly and actively inhibited the transcriptional activation of iNOS and COX-2. Western blotting, reverse transcription-polymerase chain reaction (PCR), and real-time PCR analyses demonstrated that acacetin significantly blocked protein and mRNA expression of iNOS and COX-2 in LPS-inducted macrophages. Treatment with acacetin reduced translocation of nuclear factor-kappa B (NF kappa B) subunit and the dependent transcriptional activity of NF kappa B. The activation of NF kappa B was inhibited by prevention of the degradation of inhibitor kappa B (I kappa B). Furthermore, acacetin inhibited LPS-induced phosphorylation as well as degradation of I kappa B alpha. We further investigated the roles of tyrosine kinase, phosphatidylinositiol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) in LPS-induced macrophages. We found that acacetin also inhibited LPS-induced activation of PI3K/Akt and p44/42, but not p38 MAPK. After initiation of 7,12-dimethlybene[a]anthracene (DMBA), applying acacentin topically before each 12-O-tetradecanoylphorbol 13-acetat (TPA) treatment was found to reduce the number of papillomas at 20 weeks. Taken together, these results show that acacetin down regulates inflammatory iNOS and COX-2 gene expression in macrophages by inhibiting the activation of NF kappa B by interfering with the activation PI3K/Akt/IKK and MAPK, suggesting that acacetin is a functionally novel agent capable of preventing inflammation-associated tumorigenesis.
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PMID:Acacetin suppressed LPS-induced up-expression of iNOS and COX-2 in murine macrophages and TPA-induced tumor promotion in mice. 1694 56

Legionella pneumophila causes community- and hospital-acquired pneumonia. Lung airway and alveolar epithelial cells comprise an important barrier against airborne pathogens. Cyclooxygenase (COX) and microsomal PGE(2) synthase-1 (mPGES-1)-derived prostaglandins like prostaglandin E(2) (PGE(2)) are considered as important regulators of lung function. Herein we tested the hypothesis that L. pneumophila induced COX-2 and mPGES-1-dependent PGE(2) production in pulmonary epithelial cells. Legionella induced the release of PGE(2) in primary human small airway epithelial cells and A549 cells. This was accompanied by an increased expression of COX-2 and mPGES-1 as well as an increased PLA(2) activity in infected cells. Deletion of the type IV secretion system Dot/Icm did not impair Legionella-related COX-2 expression or PGE(2) release in A549 cells. L. pneumophila induced the degradation of IkappaBalpha and activated NF-kappaB. Inhibition of IKK blocked L. pneumophila-induced PGE(2) release and COX-2 expression. We noted activation of p38 and p42/44 MAP kinase in Legionella-infected A549 cells. Moreover, membrane translocation and activation of PKCalpha was observed in infected cells. PKCalpha and p38 and p42/44 MAP kinase inhibitors reduced PGE(2) release and COX-2 expression. In summary, PKCalpha and p38 and p42/44 MAP kinase controlled COX-2 expression and subsequent PGE(2) release by Legionella-infected lung epithelial cells. These pathways may significantly contribute to the host response in Legionnaires' disease.
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PMID:Legionella pneumophila-induced PKCalpha-, MAPK-, and NF-kappaB-dependent COX-2 expression in human lung epithelium. 1701 71

Toll-like receptors (TLRs), which are activated by invading microorganisms or endogenous molecules, evoke immune and inflammatory responses. TLR activation is closely linked to the development of many chronic inflammatory diseases including rheumatoid arthritis. Auranofin, an Au(I) compound, is a well-known and long-used anti-rheumatic drug. However, the mechanism as to how auranofin relieves the symptom of rheumatoid arthritis has not been fully clarified. Our results demonstrated that auranofin suppressed TLR4-mediated activation of transcription factors, NF-kappaB and IRF3, and expression of COX-2, a pro-inflammatory enzyme. This suppression was well correlated with the inhibitory effect of auranofin on the homodimerization of TLR4 induced by an agonist. Furthermore, auranofin inhibited NF-kappaB activation induced by MyD88-dependent downstream signaling components of TLR4, MyD88, IKKbeta, and p65. IRF3 activation induced by MyD88-independent signaling components, TRIF and TBK1, was also downregulated by auranofin. Our results first demonstrate that auranofin suppresses the multiple steps in TLR4 signaling, especially the homodimerization of TLR4. The results suggest that the suppression of TLR4 activity by auranofin may be the molecular mechanism through which auranofin exerts anti-rheumatic activity.
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PMID:Auranofin, as an anti-rheumatic gold compound, suppresses LPS-induced homodimerization of TLR4. 1703 61

We previously found that bee venom (BV) and melittin (a major component of BV) has anti-inflammatory effect by reacting with the sulfhydryl group of p50 of NF-kappaB. Since the sulfhydryl group is present in IkappaB kinase (IKKalpha and IKKbeta), anti-inflammatory effect of melittin via interaction with IKKs was investigated. We first examined binding of melittin to IKKs using surface plasmon resonance analyzer. Melittin binds to IKKalpha (K(d) = 1.34 x 10(-9) M) and IKKbeta (K(d) = 1.01 x 10(-9) M). Consistent with the high binding affinity, melittin (5 and 10 microg/ml) and BV (0.5, 1 and 5 microg/ml) suppressed sodium nitroprusside, TNF-alpha and LPS induced-IKKbeta and IKKbeta activities, IkappaB release, and NF-kappaB activity as well as the expressions of iNOS and COX-2, and the generation of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) in Raw 264.7 mouse macrophages and synoviocytes obtained from rheumatoid arthritis patients. The binding affinities of melittin to mutant IKKs, was reduced, and the inhibitory effect of melittin on IKK and NF-kappaB activities, and NO and PGE(2) generation were abrogated by the reducing agents or in Raw 264.7 transfected with mutant plasmid IKKalpha (C178A) or IKKbeta (C179A). These results suggest that melittin binding to the sulfhydryl group of IKKs resulted in reduced IKK activities, IkappaB release, NF-kappaB activity and generation of inflammatory mediators, indicating that IKKs may be also anti-inflammatory targets of BV.
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PMID:Melittin inhibits inflammatory target gene expression and mediator generation via interaction with IkappaB kinase. 1706 57

AP-1/cJun, NF-kappaB and STAT3 transcription factors control expression of numerous genes, which regulate critical cell functions including proliferation, survival and apoptosis. Sodium arsenite is known to suppress both the IKK-NF-kappaB and JAK2-STAT3 signaling pathways and to activate the MAPK/JNK-cJun pathways, thereby committing some cancers to undergo apoptosis. Indeed, sodium arsenite is an effective drug for the treatment of acute promyelocytic leukemia with little nonspecific toxicity. Malignant melanoma is highly refractory to conventional radio- and chemotherapy. In the present study, we observed strong effects of sodium arsenite treatment on upregulation of TRAIL-mediated apoptosis in human and mouse melanomas. Arsenite treatment upregulated surface levels of death receptors, TRAIL-R1 and TRAIL-R2, through increased translocation of these proteins from cytoplasm to the cell surface. Furthermore, activation of cJun and suppression of NF-kappaB by sodium arsenite resulted in upregulation of the endogenous TRAIL and downregulation of the cFLIP gene expression (which encodes one of the main anti-apoptotic proteins in melanomas) followed by cFLIP protein degradation and, finally, by acceleration of TRAIL-induced apoptosis. Direct suppression of cFLIP expression by cFLIP RNAi also accelerated TRAIL-induced apoptosis in these melanomas, while COX-2 suppression substantially increased levels of both TRAIL-induced and arsenite-induced apoptosis. In contrast, overexpression of permanently active AKTmyr inhibited TRAIL-mediated apoptosis via downregulation of TRAIL-R1 levels. Finally, AKT overactivation increased melanoma survival in cell culture and dramatically accelerated growth of melanoma transplant in vivo, highlighting a role of AKT suppression for effective anticancer treatment.
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PMID:Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression. 1707 May 20

Endothelial cells are important reservoirs for human cytomegalovirus (HCMV) replication, dissemination and persistence. HCMV infection of endothelial cells has been associated with a proinflammatory response characterized by an increased expression of chemokines and adhesion molecules and modulation of angiogenesis. Many of the host proinflammatory genes augmented in HCMV-infected endothelial cells are regulated, at least in part, by the NF-kappaB pathway. HCMV is a potent activator of NF-kappaB through the IKK-IkappaB signaling axis. To explore whether inhibition of HCMV-induced NF-kappaB activation may interfere with the onset of virus-associated inflammatory response, we measured the effects of the specific IKK2 inhibitor AS602868 on the expression of a panel of proinflammatory genes in HUVEC cells infected with a clinical isolate. Treatment of infected HUVEC with AS602868 was shown to impair HCMV-induced NF-kappaB activity, IE gene expression, viral replication and to prevent HCMV-induced upregulation of ICAM-1, IL-8, RANTES, IP-10, I-TAC and COX-2 gene expression. Consistent with these results, HCMV-mediated upregulation of another NF-kappaB-dependent gene, the plasminogen inhibitor type-1, a regulatory factor of endothelial proliferation and angiogenesis, was abrogated by AS602868. These results suggest that inhibition of HCMV-induced IKK-NF-kappaB activation may be of interest to limit the virus-induced inflammatory response of infected endothelial cells.
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PMID:Targeting the NF-kappaB pathway through pharmacological inhibition of IKK2 prevents human cytomegalovirus replication and virus-induced inflammatory response in infected endothelial cells. 1707 Jun 4

Celastrol, a quinone methide triterpene derived from the medicinal plant Tripterygium wilfordii, has been used to treat chronic inflammatory and autoimmune diseases, but its mechanism is not well understood. Therefore, we investigated the effects of celastrol on cellular responses activated by TNF, a potent proinflammatory cytokine. Celastrol potentiated the apoptosis induced by TNF and chemotherapeutic agents and inhibited invasion, both regulated by NF-kappaB activation. We found that TNF induced the expression of gene products involved in antiapoptosis (IAP1, IAP2, Bcl-2, Bcl-XL, c-FLIP, and survivin), proliferation (cyclin D1 and COX-2), invasion (MMP-9), and angiogenesis (VEGF) and that celastrol treatment suppressed their expression. Because these gene products are regulated by NF-kappaB, we postulated that celastrol mediates its effects by modulating the NF-kappaB pathway. We found that celastrol suppressed both inducible and constitutive NF-kappaB activation. Celastrol was found to inhibit the TNF-induced activation of IkappaBalpha kinase, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 nuclear translocation and phosphorylation, and NF-kappaB-mediated reporter gene expression. Recent studies indicate that TNF-induced IKK activation requires activation of TAK1, and we indeed found that celastrol inhibited the TAK1-induced NF-kappaB activation. Overall, our results suggest that celastrol potentiates TNF-induced apoptosis and inhibits invasion through suppression of the NF-kappaB pathway.
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PMID:Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-kappaB-regulated gene products and TAK1-mediated NF-kappaB activation. 1711 Apr 49

The brain is one of the major target organs of ethanol actions, and its chronic and acute intoxication results in significant alterations in brain structure and function, and in some cases to neurodegeneration. Glial cells and Toll-like receptors (TLRs) are vital players in CNS immune response; dysregulation of this response plays an important role in brain damage and neurodegeneration. Ethanol has immunomodulatory effects and induces specific alterations in the TLRs response in many tissues. These actions depend on the cell type, ethanol dose and treatment duration, as well as the concomitant presence of pathogens and their characteristics. Recent findings indicate that low concentrations of ethanol (10 mM) promote inflammatory processes in brain and in glial cells by up-regulating cytokines and inflammatory mediators (iNOS, NO, COX-2), and by activating signaling pathways (IKK, MAPKs) and transcriptional factors (NF-kappaB, AP-1) implicated in inflammatory injury. TLR4/IL-1RI receptors may be involved in ethanol-mediated inflammatory signaling, since blocking these receptors abolishes the production of ethanol-induced inflammatory mediators and cell death. We propose that at low physiologically relevant concentrations, ethanol facilitates TLR4/IL-1RI recruitment into lipid rafts microdomains, leading to the activation and signaling of these receptors. In summary, current results suggest that TLR4/ IL-1RI are important targets of ethanol-induced inflammatory brain damage.
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PMID:Ethanol intake enhances inflammatory mediators in brain: role of glial cells and TLR4/IL-1RI receptors. 1712 67

Redox sensitive, pro-inflammatory nuclear transcription factor NF-kappaB plays a key role in both inflammation and aging processes. In a redox state disrupted by oxidative stress, pro-inflammatory genes are upregulated by the activation of NF-kappaB through diverse kinases. Thus, the search and characterization of new substances that modulate NF-kappaB are of recent research interest. Cinnamaldehyde (CNA) is the major component of cinnamon bark oil, which has been widely used as a flavoring agent in foodstuffs such as beverages and ice cream. In the present study, CNA was examined for its molecular modulation of inflammatory NF-kappaB activation via the redox-related NIK/IKK and MAPK pathways through the reduction of oxidative stress. Results show that age-related NF-kappaB activation upregulated NF-kappaB targeting genes, inflammatory iNOS, and COX-2, all of which were inhibited effectively by CNA. Our study further shows that CNA inhibited the activation of NF-kappaB via three signal transduction pathways, NIK/IKK, ERK, and p38 MAPK. Our results indicate that CNA's antioxidative effect and the restoration of redox balance were responsible for its anti-inflammatory action. Thus, the significance of the current study is the new information revealing the anti-inflammatory properties of CNA and the role it plays in the regulation of age-related alterations in signal transduction pathways.
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PMID:Suppression of age-related inflammatory NF-kappaB activation by cinnamaldehyde. 1748 22

Gambogic acid (GA), a xanthone derived from the resin of the Garcinia hanburyi, has been recently demonstrated to bind transferrin receptor and exhibit potential anticancer effects through a signaling mechanism that is not fully understood. Because of the critical role of NF-kappaB signaling pathway, we investigated the effects of GA on NF-kappaB-mediated cellular responses and NF-kappaB-regulated gene products in human leukemia cancer cells. Treatment of cells with GA enhanced apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents, inhibited the expression of gene products involved in antiapoptosis (IAP1 and IAP2, Bcl-2, Bcl-x(L), and TRAF1), proliferation (cyclin D1 and c-Myc), invasion (COX-2 and MMP-9), and angiogenesis (VEGF), all of which are known to be regulated by NF-kappaB. GA suppressed NF-kappaB activation induced by various inflammatory agents and carcinogens and this, accompanied by the inhibition of TAK1/TAB1-mediated IKK activation, inhibited IkappaBalpha phosphorylation and degradation, suppressed p65 phosphorylation and nuclear translocation, and finally abrogated NF-kappaB-dependent reporter gene expression. The NF-kappaB activation induced by TNFR1, TRADD, TRAF2, NIK, TAK1/TAB1, and IKKbeta was also inhibited. The effect of GA mediated through transferrin receptor as down-regulation of the receptor by RNA interference reversed its effects on NF-kappaB and apoptosis. Overall our results demonstrate that GA inhibits NF-kappaB signaling pathway and potentiates apoptosis through its interaction with the transferrin receptor.
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PMID:Gambogic acid, a novel ligand for transferrin receptor, potentiates TNF-induced apoptosis through modulation of the nuclear factor-kappaB signaling pathway. 2364 Sep 97


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