Molecular activation of NF-κB, pro-inflammatory mediators, and signal pathways in γ-irradiated mice

Ha, Young Mi; Chung, Sang Woon; Kim, Ji Min; Kim, Dae Hyun; Lee, Eun Kyeong; Lee, Jaewon; Kim, Young Jin; Yoo, Mi‐Ae; Jeong, Kyu Shik; Chung, Hae Young

doi:10.1007/s10529-009-0165-4

Cited by 21 publications

(12 citation statements)

References 18 publications

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“…For example, irradiation has been shown to increase oxidative stress, which activates inflammatory functions such as those governed by NF-kB signaling and the AP-1 complex. 38, 39 Genes involved in the transcription factor regulation of immune components, such as those associated with NF-kB, were identified as differentially expressed in haNK cells by irradiation exposure. It has been shown that irradiation of the parent NK-92 cells halted their proliferation while both cytotoxicity and immune signaling functions remained intact.…”

Section: Discussionmentioning

confidence: 99%

ADCC employing an NK cell line (haNK) expressing the high affinity CD16 allele with avelumab, an anti-PD-L1 antibody

et al. 2017

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NK-92 cells, and their derivative, designated aNK, were obtained from a patient with non-Hodgkin lymphoma. Prior clinical studies employing adoptively transferred irradiated aNK cells have provided evidence of clinical benefit and an acceptable safety profile. aNK cells have now been engineered to express IL-2 and the high affinity (ha) CD16 allele (designated haNK). Avelumab is a human IgG1 anti–PD-L1 monoclonal antibody, which has shown evidence of clinical activity in a range of human tumors. Prior in vitro studies have shown that avelumab has the ability to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) of human tumor cells when combined with NK cells. In the studies reported here, the ability of avelumab to enhance the lysis of a range of human carcinoma cells by irradiated haNK cells via the ADCC mechanism is demonstrated; this ADCC is shown to be inhibited by anti-CD16 blocking antibody and by concanamycin A, indicating the use of the granzyme/perforin pathway in tumor cell lysis. Studies also show that while NK cells have the ability to lyse aNK or haNK cells, the addition of NK cells to irradiated haNK cells does not inhibit haNK-mediated lysis of human tumor cells, with or without the addition of avelumab. Avelumab-mediated lysis of tumor cells by irradiated haNK cells is also shown to be similar to that of NK cells bearing the V/V Fc receptor high affinity allele. These studies thus provide the rationale for the clinical evaluation of the combined use of avelumab with that of irradiated adoptively transferred haNK cells.

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Section: Discussionmentioning

confidence: 99%

ADCC employing an NK cell line (haNK) expressing the high affinity CD16 allele with avelumab, an anti-PD-L1 antibody

et al. 2017

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“…Of particular relevance in ROS/iron metabolism are the facts that NF-κB is redox-sensitive (e.g. Aggarwal and Sung 2009; Baeuerle and Henkel 1994; Chandrasekaran and Taylor 2008; Cho et al 1998; Dröge 2002; Fulda et al 2010; Galaris et al 2008; Gloire et al 2006; Gloire and Piette 2009; Ha et al 2010; Haddad et al 2000; Hayashi et al 1993; Janssen-Heininger et al 2008; Lagan et al 2008; Lukosz et al 2010; Nishi et al 2002; Phillips et al 2010; Schreck et al 1991, 1992; Schreck and Baeuerle 1994; Sen and Packer 1996; She et al 2002; Surh et al 2005; Surh and Na 2008; Thannickal and Fanburg 2000; Trachootham et al 2008, 2009; Valko et al 2007; Weinberg and Chandel 2009; Wondrak 2009; Xiong et al 2003) and that there are links between NF-κB and NGAL/lcn2 (Bu et al 2006; Cowland et al 2003, 2006, 2008; Karlsen et al 2010) and/or hepcidin (Sow et al 2009; Tacchini et al 2008). Specificity is likely to come, in part, via the frequency encoding of NF-κB activity (Ashall et al 2009; Nelson et al 2004).…”

Section: Inflammation and Nf-κbmentioning

confidence: 99%

Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples

2010

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Exposure to a variety of toxins and/or infectious agents leads to disease, degeneration and death, often characterised by circumstances in which cells or tissues do not merely die and cease to function but may be more or less entirely obliterated. It is then legitimate to ask the question as to whether, despite the many kinds of agent involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evidence that in a great many cases, one underlying mechanism, providing major stresses of this type, entails continuing and autocatalytic production (based on positive feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell death via apoptosis (probably including via pathways induced by changes in the NF-κB system). While every pathway is in some sense connected to every other one, I highlight the literature evidence suggesting that the degenerative effects of many diseases and toxicological insults converge on iron dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances (probably in partnership with appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions.

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“…Damaging effects of IR are generally mediated through the production of reactive species (RS), and a substantial increase in RS levels induces cellular damage and decrease in antioxidant enzymes, as well as activates intracellular signaling pathways that activate the expression of many inflammatory genes. The IR induced molecular responses may also be characterized as increased cyclooxygenase-2 (COX-2) level, inducible nitric oxide synthase (iNOS) and vascular adhesion molecule-1 (VCAM-1) expressions that also initiates the activation of the transcription factor NF-κB 266 . The key role played by NF-κB activation in the process of inflammation has been reported to be closely associated with a redox-sensitive signal cascade that includes MAPKs (ERK, c-Jun Nterminal kinase (JNK] and p38) and Akt 266,267 .…”

Section: Radiation Countermeasures In Relation To Nf-mentioning

confidence: 99%

“…The IR induced molecular responses may also be characterized as increased cyclooxygenase-2 (COX-2) level, inducible nitric oxide synthase (iNOS) and vascular adhesion molecule-1 (VCAM-1) expressions that also initiates the activation of the transcription factor NF-κB 266 . The key role played by NF-κB activation in the process of inflammation has been reported to be closely associated with a redox-sensitive signal cascade that includes MAPKs (ERK, c-Jun Nterminal kinase (JNK] and p38) and Akt 266,267 . However, activation of the Akt signaling pathway has been known to reduce forkhead box-O (FOXO) transcription activity 268 , and is involved in cytoprotective effects against oxidative stress 269 .…”

Section: Radiation Countermeasures In Relation To Nf-mentioning

confidence: 99%

NF-κB as a key player in regulation of cellular radiation responses and identification of radiation countermeasures

2015

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Nuclear factor (NF)-κB is a transcription factor that plays significant role in immunity, cellular survival and inhibition of apoptosis, through the induction of genetic networks. Depending on the stimulus and the cell type, the members of NF-κB related family (RelA, c-Rel, RelB, p50, and p52), forms different combinations of homo and hetero-dimers. The activated complexes (Es) translocate into the nucleus and bind to the 10bp κB site of promoter region of target genes in stimulus specific manner.

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Molecular activation of NF-κB, pro-inflammatory mediators, and signal pathways in γ-irradiated mice

Cited by 21 publications

References 18 publications

ADCC employing an NK cell line (haNK) expressing the high affinity CD16 allele with avelumab, an anti-PD-L1 antibody

ADCC employing an NK cell line (haNK) expressing the high affinity CD16 allele with avelumab, an anti-PD-L1 antibody

Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples

NF-κB as a key player in regulation of cellular radiation responses and identification of radiation countermeasures

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