{"id":{"repo_id":"utmb","oai_identifier":"oai:utmb-ir.tdl.org:2152.3/115"},"canonical_url":"https://search.dev.ndltd.org/etd/utmb/oai:utmb-ir.tdl.org:2152.3/115","repository":{"repo_id":"utmb","name":"University of Texas Medical Branch","base_url":"https://utmb-ir.tdl.org/server/oai/request"},"display":{"title":"IL-1 activation of NF-kB contributes to perinatal hypoxia/ischemia induced cell death","abstract":"IL-1 activity has been implicated in perinatal hypoxia/ischemia (HI) brain damage without the underlying mechanisms being characterized. We used a 7-day-old rat model to elucidate the role of NF-kB in HI stimulation of IL-1 signaling. HI was induced by permanent ligation of the left carotid artery followed by 90 minutes of hypoxia (7.8% O2). We observed increased cell death and caspase 3 activity in the hippocampus and the cortex 3 to 48h post-HI. IL-1beta protein expression increased began at 3h after HI and lasted until 24h post-HI in the hippocampus and 12h post-HI in the cortex. Intracerebroventricular injection of 2mg IL-1 receptor antagonist (IL-1Ra) 2h post-HI significantly reduced cell death and caspase 3 activity. EMSA analyses for NF-kB activity showed increased p65/p50 DNA-binding activity at 24h post-HI. Western blot analyses and immunofluorescent staining showed significant nuclear translocation of p65. Protein expression levels of iNOS and COX2, known to be transcriptionally regulated by NF-kB, also increased at 24h post-HI. All these changes were reversed by IL-1Ra blockade of IL-1, consistent with IL-1 triggering of inflammatory apoptotic outcomes via NF-kB transcriptional activation. The observed increase in cytoplasmic phosphorylated IkBa and nuclear translocation of Bcl-3, was also attenuated by IL-1Ra blockade, suggesting that HI-induced IL-1 activation of NF-kB is via both degradation of IkBalpha and nuclear translocation of Bcl-3. \\r\\nInhibition of NF-kB via decoys containing NF-kB binding consensus sequences present in IgG-kB promoter showed specific inhibition of p65/p50 binding activity, while Bcl-x decoys specifically inhibited c-Rel/p50 (p52) binding activity. RPAs showed that IgG-kB decoys significantly decreased IL-1alpha, TNF-alpha and TNF-beta mRNA levels compared to minimal changes after Bcl-x or scrambled decoy treatment, indicating a specific IgG-kB decoy effect on inflammation post-HI. Microarray data indicated that 1) Genes that were significantly downregulated by IgG-kB decoys were not affected by Bcl-x decoys and vice versa, another piece of evidence for selective effects of different decoys. 2) A large number of cell death/survival related genes were affected by IgG-kB decoys, confounding the final outcomes. Our results suggest that IgG-kB decoys selectively inhibit inflammatory responses to HI. However, careful design of decoy sequences is essential to acquire selective effects on cell death.","abstract_html":"IL-1 activity has been implicated in perinatal hypoxia/ischemia (HI) brain damage without the underlying mechanisms being characterized. We used a 7-day-old rat model to elucidate the role of NF-kB in HI stimulation of IL-1 signaling. HI was induced by permanent ligation of the left carotid artery followed by 90 minutes of hypoxia (7.8% O2). We observed increased cell death and caspase 3 activity in the hippocampus and the cortex 3 to 48h post-HI. IL-1beta protein expression increased began at 3h after HI and lasted until 24h post-HI in the hippocampus and 12h post-HI in the cortex. Intracerebroventricular injection of 2mg IL-1 receptor antagonist (IL-1Ra) 2h post-HI significantly reduced cell death and caspase 3 activity. EMSA analyses for NF-kB activity showed increased p65/p50 DNA-binding activity at 24h post-HI. Western blot analyses and immunofluorescent staining showed significant nuclear translocation of p65. Protein expression levels of iNOS and COX2, known to be transcriptionally regulated by NF-kB, also increased at 24h post-HI. All these changes were reversed by IL-1Ra blockade of IL-1, consistent with IL-1 triggering of inflammatory apoptotic outcomes via NF-kB transcriptional activation. The observed increase in cytoplasmic phosphorylated IkBa and nuclear translocation of Bcl-3, was also attenuated by IL-1Ra blockade, suggesting that HI-induced IL-1 activation of NF-kB is via both degradation of IkBalpha and nuclear translocation of Bcl-3. \\r\\nInhibition of NF-kB via decoys containing NF-kB binding consensus sequences present in IgG-kB promoter showed specific inhibition of p65/p50 binding activity, while Bcl-x decoys specifically inhibited c-Rel/p50 (p52) binding activity. RPAs showed that IgG-kB decoys significantly decreased IL-1alpha, TNF-alpha and TNF-beta mRNA levels compared to minimal changes after Bcl-x or scrambled decoy treatment, indicating a specific IgG-kB decoy effect on inflammation post-HI. Microarray data indicated that 1) Genes that were significantly downregulated by IgG-kB decoys were not affected by Bcl-x decoys and vice versa, another piece of evidence for selective effects of different decoys. 2) A large number of cell death/survival related genes were affected by IgG-kB decoys, confounding the final outcomes. Our results suggest that IgG-kB decoys selectively inhibit inflammatory responses to HI. However, careful design of decoy sequences is essential to acquire selective effects on cell death.","abstract_has_math":false,"creators":["Xiaoming Hu"],"institution":"The University of Texas Medical Branch","degree_name":"PhD","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["J. R. Perez-Polo,"],"committee_chairs":[],"committee_members":["Olivera B. Nesic-Taylor","Norbert K. Herzog","Marjorie R. Grafe","Karin W. High","David K Rassin"],"year":2005,"date_issued":"2005-06-01","date_published":"2005-06-01","updated_at":"2026-07-24T05:51:04Z","subjects":["IL-1","decoys","hypoxia/ischemia"],"languages":["eng"],"rights":["Copyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works."],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["etd-06082005-144039"],"render_values":[{"text":"etd-06082005-144039","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/2152.3/115","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["J. R. Perez-Polo,"]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Olivera B. Nesic-Taylor","Norbert K. Herzog","Marjorie R. Grafe","Karin W. High","David K Rassin"]},{"key":"dc:creator","label":"Author","values":["Xiaoming Hu"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2011-12-20T16:04:42Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2008-06-17","2011-12-20T16:04:42Z"]},{"key":"dc:date.issued","label":"Date","values":["2005-06-01"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["PhD"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["The University of Texas Medical Branch"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["IL-1","decoys","hypoxia/ischemia"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["etd-06082005-144039"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/2152.3/115"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["IL-1 activity has been implicated in perinatal hypoxia/ischemia (HI) brain damage without the underlying mechanisms being characterized. We used a 7-day-old rat model to elucidate the role of NF-kB in HI stimulation of IL-1 signaling. HI was induced by permanent ligation of the left carotid artery followed by 90 minutes of hypoxia (7.8% O2). We observed increased cell death and caspase 3 activity in the hippocampus and the cortex 3 to 48h post-HI. IL-1beta protein expression increased began at 3h after HI and lasted until 24h post-HI in the hippocampus and 12h post-HI in the cortex. Intracerebroventricular injection of 2mg IL-1 receptor antagonist (IL-1Ra) 2h post-HI significantly reduced cell death and caspase 3 activity. EMSA analyses for NF-kB activity showed increased p65/p50 DNA-binding activity at 24h post-HI. Western blot analyses and immunofluorescent staining showed significant nuclear translocation of p65. Protein expression levels of iNOS and COX2, known to be transcriptionally regulated by NF-kB, also increased at 24h post-HI. All these changes were reversed by IL-1Ra blockade of IL-1, consistent with IL-1 triggering of inflammatory apoptotic outcomes via NF-kB transcriptional activation. The observed increase in cytoplasmic phosphorylated IkBa and nuclear translocation of Bcl-3, was also attenuated by IL-1Ra blockade, suggesting that HI-induced IL-1 activation of NF-kB is via both degradation of IkBalpha and nuclear translocation of Bcl-3. \\r\\nInhibition of NF-kB via decoys containing NF-kB binding consensus sequences present in IgG-kB promoter showed specific inhibition of p65/p50 binding activity, while Bcl-x decoys specifically inhibited c-Rel/p50 (p52) binding activity. RPAs showed that IgG-kB decoys significantly decreased IL-1alpha, TNF-alpha and TNF-beta mRNA levels compared to minimal changes after Bcl-x or scrambled decoy treatment, indicating a specific IgG-kB decoy effect on inflammation post-HI. Microarray data indicated that 1) Genes that were significantly downregulated by IgG-kB decoys were not affected by Bcl-x decoys and vice versa, another piece of evidence for selective effects of different decoys. 2) A large number of cell death/survival related genes were affected by IgG-kB decoys, confounding the final outcomes. Our results suggest that IgG-kB decoys selectively inhibit inflammatory responses to HI. However, careful design of decoy sequences is essential to acquire selective effects on cell death."]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["electronic"]},{"key":"dc:title","label":"Title","values":["IL-1 activation of NF-kB contributes to perinatal hypoxia/ischemia induced cell death"]}]}],"canonical_facts":{"dc:contributor.advisor":["J. R. Perez-Polo,"],"dc:contributor.committeemember":["Olivera B. Nesic-Taylor","Norbert K. Herzog","Marjorie R. Grafe","Karin W. High","David K Rassin"],"dc:creator":["Xiaoming Hu"],"dc:date.accessioned":["2011-12-20T16:04:42Z"],"dc:date.available":["2008-06-17","2011-12-20T16:04:42Z"],"dc:date.issued":["2005-06-01"],"dc:description.abstract":["IL-1 activity has been implicated in perinatal hypoxia/ischemia (HI) brain damage without the underlying mechanisms being characterized. We used a 7-day-old rat model to elucidate the role of NF-kB in HI stimulation of IL-1 signaling. HI was induced by permanent ligation of the left carotid artery followed by 90 minutes of hypoxia (7.8% O2). We observed increased cell death and caspase 3 activity in the hippocampus and the cortex 3 to 48h post-HI. IL-1beta protein expression increased began at 3h after HI and lasted until 24h post-HI in the hippocampus and 12h post-HI in the cortex. Intracerebroventricular injection of 2mg IL-1 receptor antagonist (IL-1Ra) 2h post-HI significantly reduced cell death and caspase 3 activity. EMSA analyses for NF-kB activity showed increased p65/p50 DNA-binding activity at 24h post-HI. Western blot analyses and immunofluorescent staining showed significant nuclear translocation of p65. Protein expression levels of iNOS and COX2, known to be transcriptionally regulated by NF-kB, also increased at 24h post-HI. All these changes were reversed by IL-1Ra blockade of IL-1, consistent with IL-1 triggering of inflammatory apoptotic outcomes via NF-kB transcriptional activation. The observed increase in cytoplasmic phosphorylated IkBa and nuclear translocation of Bcl-3, was also attenuated by IL-1Ra blockade, suggesting that HI-induced IL-1 activation of NF-kB is via both degradation of IkBalpha and nuclear translocation of Bcl-3. \\r\\nInhibition of NF-kB via decoys containing NF-kB binding consensus sequences present in IgG-kB promoter showed specific inhibition of p65/p50 binding activity, while Bcl-x decoys specifically inhibited c-Rel/p50 (p52) binding activity. RPAs showed that IgG-kB decoys significantly decreased IL-1alpha, TNF-alpha and TNF-beta mRNA levels compared to minimal changes after Bcl-x or scrambled decoy treatment, indicating a specific IgG-kB decoy effect on inflammation post-HI. Microarray data indicated that 1) Genes that were significantly downregulated by IgG-kB decoys were not affected by Bcl-x decoys and vice versa, another piece of evidence for selective effects of different decoys. 2) A large number of cell death/survival related genes were affected by IgG-kB decoys, confounding the final outcomes. Our results suggest that IgG-kB decoys selectively inhibit inflammatory responses to HI. However, careful design of decoy sequences is essential to acquire selective effects on cell death."],"dc:format.medium":["electronic"],"dc:identifier.other":["etd-06082005-144039"],"dc:identifier.uri":["http://hdl.handle.net/2152.3/115"],"dc:language.iso":["eng"],"dc:rights":["Copyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works."],"dc:subject":["IL-1","decoys","hypoxia/ischemia"],"dc:title":["IL-1 activation of NF-kB contributes to perinatal hypoxia/ischemia induced cell death"],"thesis:degree_level":["Doctoral"],"thesis:degree_name":["PhD"],"thesis:institution_name":["The University of Texas Medical Branch"]},"updated_at":"2026-07-24T05:51:04Z"}