Article

A cytokine responsive I B kinase that activates the transcription factor NF- B

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California at San Diego, La Jolla 92093-0636, USA.
Nature (Impact Factor: 42.35). 09/1997; 388(6642):548-54. DOI: 10.1038/41493
Source: PubMed

ABSTRACT Nuclear transcription factors of the NF-kappaB/Rel family are inhibited by IkappaB proteins, which inactivate NF-kappaB by trapping it in the cell cytoplasm. Phosphorylation of IkappaBs marks them out for destruction, thereby relieving their inhibitory effect on NF-kappaB. A cytokine-activated protein kinase complex, IKK (for IkappaB kinase), has now been purified that phosphorylates IkappaBs on the sites that trigger their degradation. A component of IKK was molecularly cloned and identified as a serine kinase. IKK turns out to be the long-sought-after protein kinase that mediates the critical regulatory step in NF-kappaB activation.

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    • "It is also associated with the regulation of intracellular level of OFRs [21]. NF-kB is a crucial transcription factor for regulating the genes responsible for the inflammatory and immune reactions in both cytoprotective and cell death pathways [22]. The expression of both immunomodulatory genes and genes involved in apoptotic processes are regulated by NFk B. It is also considered as a principal mediator of the systemic inflammation in the case of IR injury. "
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    ABSTRACT: Background: Spironolactone (Sp), a mineralocorticoid receptor antagonist, protects against the ischemia reperfusion (IR) injury of retina, kidney, heart, and brain. We aimed to investigate the effects of Sp on intestinal IR injury. Methods: Male Wistar rats were randomly divided into: (1) a sham control group; (2) an IR control group, subjected to 30 min ischemia and 3 h reperfusion; (3) a group treated with Sp (20 mg/kg) for 3 d before the IR; and (4) a sham-operated control group treated with Sp (20 mg/kg). After the reperfusion, blood and intestinal tissue samples were collected to evaluate histopathologic state, neutrophil infiltration (by measuring myeloperoxidase activity), levels of the cytokines (tumor necrosis factor alpha, interleukin 1 alpha [IL-1 alpha], interferon gamma, monocyte chemotactic protein-1, granulocyte macrophage-colony stimulating factor, and IL-4), malondialdehyde (MDA) and reduced glutathione contents, and immunohistochemical expressions of nuclear factor kappa B, inducible nitric oxide synthase (iNOS), and caspase-3. Results: MDA content, myeloperoxidase activity, and plasma levels of tumor necrosis factor alpha, IL-1 alpha, and monocyte chemotactic protein-1 were all elevated in IR, indicating the oxidative stress and local and systemic inflammatory response. Sp administration markedly reduced the MDA content and the cytokine levels. The pretreatment alleviated intestinal injury, neutrophil infiltration, and the expressions of caspase-3, iNOS, and NF kappa B. Conclusions: The results implicate that Sp may have a strong protective effect against the intestinal IR injury. The effect can be mediated via suppression of both systemic inflammatory response and apoptosis through amelioration of oxidative stress and generation of proinflammatory cytokines, iNOS, caspase-3, and nuclear factor kappa B. Therefore, mineralocorticoid receptor antagonism might be of potential therapeutic benefit in cases of intestinal IR damage.
    Journal of Surgical Research 05/2014; DOI:10.1016/j.jss.2014.04.040 · 2.12 Impact Factor
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    • "It is also associated with the regulation of intracellular level of OFRs [21]. NF-kB is a crucial transcription factor for regulating the genes responsible for the inflammatory and immune reactions in both cytoprotective and cell death pathways [22]. The expression of both immunomodulatory genes and genes involved in apoptotic processes are regulated by NFk B. It is also considered as a principal mediator of the systemic inflammation in the case of IR injury. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Spironolactone (Sp), a mineralocorticoid receptor antagonist, protects against the ischemia reperfusion (IR) injury of retina, kidney, heart, and brain. We aimed to investigate the effects of Sp on intestinal IR injury. Methods Male Wistar rats were randomly divided into: (1) a sham control group; (2) an IR control group, subjected to 30 min ischemia and 3 h reperfusion; (3) a group treated with Sp (20 mg/kg) for 3 d before the IR; and (4) a sham-operated control group treated with Sp (20 mg/kg). After the reperfusion, blood and intestinal tissue samples were collected to evaluate histopathologic state, neutrophil infiltration (by measuring myeloperoxidase activity), levels of the cytokines (tumor necrosis factor α, interleukin 1α [IL-1α], interferon γ, monocyte chemotactic protein-1, granulocyte macrophage-colony stimulating factor, and IL-4), malondialdehyde (MDA) and reduced glutathione contents, and immunohistochemical expressions of nuclear factor κB, inducible nitric oxide synthase (iNOS), and caspase-3. Results MDA content, myeloperoxidase activity, and plasma levels of tumor necrosis factor α, IL-1α, and monocyte chemotactic protein-1 were all elevated in IR, indicating the oxidative stress and local and systemic inflammatory response. Sp administration markedly reduced the MDA content and the cytokine levels. The pretreatment alleviated intestinal injury, neutrophil infiltration, and the expressions of caspase-3, iNOS, and NFκB. Conclusions The results implicate that Sp may have a strong protective effect against the intestinal IR injury. The effect can be mediated via suppression of both systemic inflammatory response and apoptosis through amelioration of oxidative stress and generation of proinflammatory cytokines, iNOS, caspase-3, and nuclear factor κB. Therefore, mineralocorticoid receptor antagonism might be of potential therapeutic benefit in cases of intestinal IR damage.
    Journal of Surgical Research 05/2014; DOI:10.1016/j.jss.2014.04.040. · 2.12 Impact Factor
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    • "IKKα and IKKβ serve as the catalytic subunits of the kinase, and IKKγ serves as the regulatory subunit; activation of IKK depends upon its phosphorylation. Ser177 and Ser181 in the activation loop of IKKβ (serine 176 and 180 in IKKα) are specific sites that, when phosphorylated, cause conformational changes, resulting in kinase activation [20], [21]. IKK-mediated phosphorylation triggers IκB and p105 polyubiquitination by the SCFβTγCP E3 ligase complex and subsequent proteasomal degradation, resulting in the release of p50-, p65-, and c-Rel-containing heterodimers and translocation into the nucleus to regulate gene transcription [22]. "
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    ABSTRACT: Nuclear factor-κB (NF-κB) plays a central role in the regulation of diverse biological processes, including immune responses, development, cell growth, and cell survival. To establish persistent infection, many viruses have evolved strategies to evade the host's antiviral immune defenses. In the case of hepatitis B virus (HBV), which can cause chronic infection in the liver, immune evasion strategies used by the virus are not fully understood. It has recently been reported that the polymerase of HBV (Pol) inhibits interferon-β (IFN-β) activity by disrupting the interaction between IKKε and the DDX3. In the current study, we found that HBV Pol suppressed NF-κB signaling, which can also contribute to IFN-β production. HBV Pol did not alter the level of NF-κB expression, but it prevented NF-κB subunits involved in both the canonical and non-canonical NF-κB pathways from entering the nucleus. Further experiments demonstrated that HBV Pol preferentially suppressed the activity of the IκB kinase (IKK) complex by disrupting the association of IKK/NEMO with Cdc37/Hsp90, which is critical for the assembly of the IKK complex and recruitment of the IKK complex to the tumor necrosis factor type 1 receptor (TNF-R1). Furthermore, we found that HBV Pol inhibited the NF-κB-mediated transcription of target genes. Taken together, it is suggested that HBV Pol could counteract host innate immune responses by interfering with two distinct signaling pathways required for IFN-β activation. Our studies therefore shed light on a potential therapeutic target for persistent infection with HBV.
    PLoS ONE 03/2014; 9(3):e91658. DOI:10.1371/journal.pone.0091658 · 3.23 Impact Factor
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