Disease relevance of Nfkbia

• We conclude that diet-induced obesity and acute HL reduce IkappaBalpha levels in rat skeletal muscle in a fiber-type-dependent manner [1].
• CONCLUSIONS: Inhibition of nuclear translocation of NF-kappaB by IkappaBalpha phosphorylation blockade could provide an effective approach to attenuation of ischemia/reperfusion injury [2].
• IkappaBalpha degradation, NF-kappaB activation, and iNOS expression were attenuated by parthenolide (3mg/kg), the active constituent of feverfew, an anti-inflammatory drug used for migraine treatment [3].
• However, hypoxia could not prevent either degradation of an inhibitory protein (IkappaBalpha) of nuclear factor-kappaB (NF-kappaB) or translocation of NF-kappaB to the nucleus, whereas heat inhibited both of the IkappaBalpha degradation and NF-kappaB translocation [4].
• Blocking of NF-kappaB activation in cytokine-exposed primary beta-cells by an adenovirus overexpressing a nondegradable form of IkappaBalpha or by pyrrolidine dithiocarbamate decreased IL-1beta-induced MCP-1 mRNA expression [5].

High impact information on Nfkbia

• Transfection of cerebrocortical neurons with a dominant interfering form of Jak2 or an IkappaBalpha super-repressor blocks EPO-mediated prevention of neuronal apoptosis [6].
• In contrast, in vitro exposure of alveolar macrophages to C5a and LPS resulted in enhanced production of TNFalpha and no increase in IkappaBalpha [7].
• We now report that in vitro exposure of neutrophils to C5a causes increased levels of IkappaBalpha, decreased NF-kappaB-dependent gene transcription of TNFalpha, and decreased lipopolysaccharide (LPS)-induced TNFalpha production [7].
• We have assessed the role of NFkappaB during liver regeneration by delivering to the liver a superrepressor of NFkappaB activity using an adenoviral vector expressing a mutated form of IkappaBalpha [8].
• Moreover, in contrast to TNF-alpha, NGF failed to phosphorylate IkappaBalpha at serine residue 32, but instead caused significant tyrosine phosphorylation [9].

Chemical compound and disease context of Nfkbia

• Transient nuclear factor kappaB (NF-kappaB) activation stimulated by interleukin-1beta may be partly dependent on proteasome activity, but not phosphorylation and ubiquitination of the IkappaBalpha molecule, in C6 glioma cells. Regulation of NF-kappaB linked to chemokine production [10].
• Superfusion of the in-situ brain with N(alpha)-L-tosyl-L-phenylalanine chloromethyl ketone (TPCK), a specific inhibitor of IKB-alpha proteolysis, attenuated greatly the spasmogenic, leukocyte rolling-endothelial cell adhesion and postcapillary hemorrhages induced by ethanol [11].
• Hyperoxia reduced nuclear factor kappaB activation in the heart during sustained ischemia and reperfusion and increased the cytoplasmatic inhibitory factor IkappaBalpha [12].
• Finally, we analysed the effect of the inhibition of IkappaBalpha degradation on glutamate-induced toxicity by using BAY 11-7082, a selective inhibitor of IkappaBalpha phosphorylation [13].
• The inhibition of NFkappaB observed in rats preconditioned with 3 min ischemia, KA5 or LIN500 treatments compared with ischemic or epileptic controls was correlated with the prevention of the inducible degradation of the inhibitory protein IkappaBalpha [14].

Biological context of Nfkbia

• Taken together, these data suggest that basal IkappaBalpha expression (and as a consequence NF-kappaB activity) is under the control of the various components of the CBF1/Notch signal transduction pathway [15].
• PTX and wortmannin, a PI3 K inhibitor, not only inhibited the PDGF-activated phosphorylation of Akt but also suppressed p70(S6 K) expression and IkappaBalpha degradation, inhibiting nuclear translocation and the DNA binding activity of NF-kappaB [16].
• In addition to CD14, rapid increases in gene expression of IkappaBalpha, IL-1beta, and TNF-alpha occurred along the meninges and ventricular ependyma [17].
• Furthermore 'in vitro' IRFI 042 (50 microM) significantly inhibited activation of NF-kappaB through inhibition of IkappaBalpha degradation, reduced the amount of TNF-alpha mRNA, decreased LPS-induced TNF-alpha release and blunted lipid peroxidation (MAL) in LPS stimulated Mphi [18].
• The effect of rapamycin appeared to be independent of the phosphatidylinositol 3-kinase/Akt-protein kinase B survival pathway, because the phosphatidylinositol 3-kinase inhibitor wortmannin neither prevented IkappaBalpha degradation nor increased apoptosis of cells incubated with TNF-alpha [19].

Anatomical context of Nfkbia

• Here, we show that when restricted to spinal cord and targeted to glial cells, lentiviral vector-mediated delivery of NF-kappaB super- repressor IkappaBalpha resulted in an inhibition of the NF-kappaB pathway activated in the rat spinal cord after sciatic nerve injury (chronic constriction injury, CCI) [20].
• Activation of deltaMEKK1:ER* in CC139 fibroblasts resulted in the rapid and sustained activation of JNK without activating ERK or p38 or promoting IkappaBalpha phosphorylation [21].
• Total and phosphorylated IkappaBalpha levels in the gastric mucosa were unaffected by aging [22].
• APDC was actually confirmed to suppress the degradation of IkappaBalpha and IkappaBbeta in microglia, indicating a role for the inhibitor of NFkappaB activation [23].
• Low levels of IkappaBalpha mRNA were found in the large blood vessels and in circumventricular organs (CVOs) of saline-injected control animals [24].

Associations of Nfkbia with chemical compounds

• Importantly, the fiber-type-dependent effects on IkappaBalpha levels could not be explained by differential accumulation of triglyceride in Sol and Vas [1].
• Activation of nuclear factor kappaB and Bcl-x survival gene expression by nerve growth factor requires tyrosine phosphorylation of IkappaBalpha [9].
• IRFI-042, a vitamin E analogue (20 mg/kg intraperitoneally 2 min after the end of bleeding), inhibited the loss of IkappaBalpha protein from the cytoplasm and blunted the increase in NF-kappaB binding activity [25].
• LPS shocked rats also had increased TNF-alpha mRNA levels, augmented liver NF-kappaB binding activity in the nucleus and decreased levels of the inhibitory protein IkappaBalpha [18].
• Cyclosporin inhibited the loss of IkappaBalpha protein from the cytoplasm and prevented NF-kappaB binding activity in the nucleus [26].

Physical interactions of Nfkbia

• The level of Nuclear Factor (kappa) inhibitor (IkappaBalpha) in liver was decreased and DNA-binding activity of Nuclear Factor-kappaB (NF-kappaB) was increased after thermal injury. p38 MAP kinase was more significantly activated in liver harvested from burn rats than from shams [27].

Regulatory relationships of Nfkbia

• Concomitantly, IkappaBalpha overproduction prevented the enhanced expression of interleukin-6 and of inducible nitric oxide synthase associated with chronic constriction injury and resulted in prolonged antihyperalgesic and antiallodynic effects [20].
• OFF also inhibited TNF-alpha-induced IkappaBalpha degradation and TNF-alpha-induced IkappaB kinase (IKK) activity in a shear stress-dependent manner [28].
• PIC signaled degradation of IkappaBalpha with the consequence of upregulating iNOS, TNF-alpha, and IL-1beta mRNAs and proteins [29].
• Infection of isolated neonatal cardiac myocytes with an adenovirus expressing a constitutively active form of Rac1 (RacV12) enhanced the expression of a kappaB-dependent reporter gene construct and induced the degradation of IkappaBalpha [30].
• In addition, we found that octyl caffeate did not significantly affect IkappaBalpha degradation stimulated by LPS/IFN-gamma in RASMCs [31].

Other interactions of Nfkbia

• In the brain parenchyma, increased TLR4 immunoreactivity was confined to the vasculature and neighboring tissues along with strong vascular expression of IkappaBalpha and mPGES-1 [17].
• HYP content in liver, the expressions of ICAM-1, VCAM-1 mRNA and protein, NF-kappaBp65 and alpha-SMA protein were decreased significantly and IkappaBalpha protein in liver was elevated significantly in this group [32].
• Basal expression of IkappaBalpha is controlled by the mammalian transcriptional repressor RBP-J (CBF1) and its activator Notch1 [15].
• SNAP also blocked cytokine- induced increase in NF-kappaB activation, iNOS promoter activity, nuclear translocation of cytosolic NF-kappaB p65 subunit, and IkappaBalpha degradation, which correlated with its inhibitory effect on phosphorylation and ubiquitination of IkappaB [33].
• Ang II treatment also resulted in the degradation of IkappaBalpha and increase of NF-kappaB p65 subunit in the nucleus as well as the DNA binding activity of nuclear NF-kappaB [34].

Analytical, diagnostic and therapeutic context of Nfkbia

• Unlike tumor necrosis factor-alpha (TNF-alpha), however, NGF-induced NFkappaB activation occurred without significant degradation of IkappaBs determined by Western blot analysis and time-lapse imaging of neurons expressing green fluorescent protein-tagged IkappaBalpha [9].
• Furthermore, electrophoretic mobility shift assay showed that liver NF-kappaB binding activity increased in the nucleus, and Western blot analysis suggested that the levels of inhibitory IkappaBalpha protein in the cytoplasm decreased [35].
• The expression of IL-1alpha, TNF-alpha and MCP-1 was measured by enzyme immunoassay (EIA), and the regulatory proteins NFkappaB and IkappaBalpha were measured by Western blot analysis [36].
• In this study, we examined the mRNA expression of IkappaBalpha and IL-1beta in the rat brain by in situ hybridization histochemistry [37].
• Immobilization of rats for 2 hr (which raises glucocorticoid levels) also induced IkappaBalpha mRNA expression without inducing the expression of IL-1beta [37].

References